Compositions and methods for adjoining type i and type ii extracellular domains as heterologous chimeric proteins

ABSTRACT

The present invention relates to, inter alia, compositions and methods, including chimeric proteins that find use in the treatment of disease, such as immunotherapies for cancer and autoimmunity. In part, the invention provides, in various embodiments, fusions of extracellular domains of transmembrane proteins that can have stimulatory or inhibitory effects.

PRIORITY

This application is a continuation of U.S. application Ser. No.15/804,533, filed Nov. 6, 2017. U.S. Ser. No. 15/804,533 is acontinuation of U.S. application Ser. No. 15/281,196, filed Sep. 30,2016. U.S. Ser. No. 15/281,196 claims the benefit of, and priority to,U.S. Provisional Application No. 62/235,727, filed Oct. 1, 2015, U.S.Provisional Application No. 62/263,313, filed Dec. 4, 2015, and U.S.Provisional Application No. 62/372,574, filed Aug. 9, 2016. The contentsof each above-mentioned application are hereby incorporated by referencein their entireties.

TECHNICAL FIELD

The present invention relates to, inter alia, compositions and methods,including chimeric proteins that find use in the treatment of disease,such as immunotherapies for cancer and autoimmunity.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

The contents of the text file submitted electronically herewith areincorporated herein by reference in their entirety: A computer readableformat copy of the Sequence Listing (filename: SHK-HTB-023C2_ST25.txt;date recorded: Dec. 22, 2017; file size: 142,758 bytes).

BACKGROUND

The interaction between cancer and the immune system is complex andmultifaceted. See de Visser et al., Nat. Rev. Cancer (2006) 6:24-37.While many cancer patients appear to develop an anti-tumor immuneresponse, cancers also develop strategies to evade immune detection anddestruction. Recently, immunotherapies have been developed for thetreatment and prevention of cancer and other disorders. Immunotherapyprovides the advantage of cell specificity that other treatmentmodalities lack. As such, methods for enhancing the efficacy of immunebased therapies can be clinically beneficial. Advances in defining themechanisms and molecules that regulate immune responses have providednovel therapeutic targets for treating cancer. For example,costimulatory and coinhibitory molecules play a central role in theregulation of T cell immune responses. However, despite impressivepatient responses to antibody agents targeting these costimulatory andcoinhibitory molecules, including for example anti-PD-1/PD-L1,checkpoint inhibition therapy still fails in many patients. Therefore,as with most cancer therapies, there remains a need for new compositionsand methods that can improve the effectiveness of these agents.

SUMMARY

Accordingly, in various aspects, the present invention provides forcompositions and methods that are useful for cancer immunotherapy, e.g.to manipulate or modify immune signals for therapeutic benefit. Invarious embodiments, the invention reverses or suppresses immuneinhibitory signals while providing immune activating or co-stimulatorysignals in a beneficial context. For instance, in one aspect, thepresent invention provides chimeric protein comprising: (a) a firstextracellular domain of a type I transmembrane protein at or near theN-terminus, (b) a second extracellular domain of a type II transmembraneprotein at or near the C-terminus, and (c) a linker, wherein one of thefirst and second extracellular domains is an immune inhibitory signaland one of the first and second extracellular domains is an immunestimulatory signal. By linking these two molecules in a functionalorientation, coordination between the positive and negative signals canbe achieved. For example, the present invention provides, in variousembodiments, masking of negative immune signals and stimulation ofpositive immune signals in a single construct. In various embodiments,provides for compositions that are not antibodies, or based uponantibody-derived antigen binding domains (e.g. complementaritydetermining regions, CDRs), but rather provide direct receptor/ligandinteraction.

In cancer patients, an immune response can be stimulated against tumorantigens to activate a patient's own immune system to kill tumor cells.However, some cancer cells devise strategies to evade an immune responsein a process known as immuno-editing. This can include down-regulationof specific antigens, down-regulation of MHC I, up-regulation of immuneregulatory surface molecules (PD-L1, PD-L2, CEACAM1, galectin-9, B7-H3,B7-H4, VISTA, CD47, etc.) or up-regulation of soluble immune inhibitorymolecules (IDO, TGF-β, MICA, etc). In general, these strategies areco-opted by tumor cells so that when tumor-infiltrating immune killercells encounter a tumor cell, those cells become directly inhibited byimmunosuppressive factors and therefore cannot kill the tumor cell. Manyof the immunosuppressive ligands co-opted by tumor cells to suppress animmune response interact with receptors that are type I membraneproteins. In some embodiments, the chimeric protein of the presentinvention comprises an extracellular domain of an immune inhibitoryagent, including without limitation, one or more of TIM-3, BTLA, PD-1,CTLA-4, B7-H4, PD-L1, PD-L2, B7-H3, CD244, TIGIT, CD172a/SIRPa,VISTA/VSIG8, CD115, CD200, CD223, and TMIGD2. In some embodiments, thechimeric protein of the present invention comprises an extracellulardomain of a type I membrane protein which has immune inhibitoryproperties. In various embodiments, the chimeric protein is engineeredto disrupt, block, reduce, and/or inhibit the transmission of an immuneinhibitory signal, by way of non-limiting example, the binding of PD-1with PD-L1 or PD-L2 and/or the binding of CD172a with CD47 and/or thebinding of TIM-3 with one or more of galectin-9 and/orphosphatidylserine.

Further, in addition to suppression of immune inhibitory signaling, itis often desirable to enhance immune stimulatory signal transmission toboost an immune response, for instance to enhance a patient's anti-tumorimmune response. In some embodiments, the chimeric protein of thepresent invention comprises an extracellular domain of an immunestimulatory signal, which, without limitation, is one or more of OX-40ligand, LIGHT (CD258), GITR ligand, CD70, CD30 ligand, CD40 ligand,CD137 ligand, TRAIL and TL1A. In some embodiments, the chimeric proteinof the present invention comprises an extracellular domain of a type IImembrane protein which has immune stimulatory properties. In variousembodiments, the chimeric protein is engineered to enhance, increase,and/or stimulate the transmission of an immune stimulatory signal, byway of non-limiting example, the binding of GITR with one or more ofGITR ligand and/or the binding of OX40 with OX40L and/or CD40 with CD40ligand.

In various embodiments, the chimeric protein comprises an immuneinhibitory receptor extracellular domain and an immune stimulatoryligand extracellular domain which can, without limitation, deliver animmune stimulation to a T cell while masking a tumor cell's immuneinhibitory signals. In various embodiments, the present chimericproteins provide improved immunotherapeutic benefits by effectivelycausing the substitution of an immune inhibitory signal for an immunestimulatory signal. For example, a chimeric protein construct comprising(i) the extracellular domain of PD-1 and (ii) extracellular domain ofOX40L, allows for the disruption of an inhibitory PD-L1/L2 signal andits replacement with a stimulating OX40L. Accordingly, the presentchimeric proteins, in some embodiments are capable of, or find use inmethods involving, reducing or eliminating an inhibitory immune signaland/or increasing or activating an immune stimulatory signal. Suchbeneficial properties are enhanced by the single construct approach ofthe present chimeric proteins. For instance, the signal replacement canbe effected nearly simultaneously and the signal replacement is tailoredto be local at a site of clinical importance (e.g. the tumormicroenvironment). Further embodiments apply the same principle to otherchimeric protein constructs, such as, for example, (i) the extracellulardomain of PD-1 and (ii) extracellular domain of GITRL; (i) theextracellular domain of BTLA and (ii) extracellular domain of OX40L; (i)the extracellular domain of TIGIT and (ii) extracellular domain ofOX40L; (i) the extracellular domain of TMIGD2 and (ii) extracellulardomain of OX40L; (i) the extracellular domain of TIM3 and (ii)extracellular domain of OX40L; and (i) the extracellular domain ofCD172a or CD115 and (ii) extracellular domain of CD40L; among others.

Further still, in some embodiments, the present chimeric proteins arecapable of, or find use in methods involving, shifting the balance ofimmune cells in favor of immune attack of a tumor. For instance, thepresent chimeric proteins can shift the ratio of immune cells at a siteof clinical importance in favor of cells that can kill a tumor (e.g. Tcells, cytotoxic T lymphocytes, T helper cells, natural killer (NK)cells, natural killer T (NKT) cells, anti-tumor macrophages (e.g. M1macrophages), B cells, and dendritic cells and in opposition to cellsthat protect tumors (e.g. myeloid-derived suppressor cells (MDSCs),regulatory T cells (Tregs); tumor associated neutrophils (TANs), M2macrophages, and tumor associated macrophages (TAMs)). In someembodiments, the present chimeric protein is capable of increasing aratio of effector T cells to regulatory T cells.

In various embodiments, the present chimeric protein unexpectedlyprovides binding of the extracellular domain components to theirrespective binding partners with longer off rates (Kd or K_(off)) andtherefore, inter alia, accords longer occupancy of the receptor toligand and vice versa. For instance, in some embodiments, this providesa sustained negative signal masking effect. Further, in someembodiments, this delivers a longer positive signal effect, e.g. toallow an effector cell to be adequately stimulated (e.g. forproliferation and/or release of stimulatory signals like cytokines).Also, this stable synapse of cells (e.g. a tumor cell bearing negativesignals and a T cell which could attack the tumor) provides spatialorientation to favor tumor reduction—such as positioning the T cells toattack tumor cells and/or sterically preventing the tumor cell fromdelivering negative signals, including negative signals beyond thosemasked by the chimeric protein of the invention. In still furtherembodiments, this provides longer on-target (e.g. intra-tumoral)half-life (t_(1/2)) as compared to serum t_(1/2) of the chimericproteins. Such properties could have the combined advantage of reducingoff-target toxicities associated with systemic distribution of thechimeric proteins.

Also in various aspects, the present chimeric protein is used in amethod for treating cancer comprising administering an effective amountof a pharmaceutical composition comprising the chimeric protein to apatient in need thereof. In further aspects, the present chimericprotein is used in a method for treating infections, including withoutlimitation, viral infections or other intracellular pathogens. In stillfurther aspects, the present chimeric protein is used in a method fortreating autoimmune diseases.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows illustrations of orientations of type I (left) and type II(right) membrane proteins in a cell membrane. In the type I membraneprotein of the left panel, the amino terminus (denoted “N”) faces theextracellular environment and the carboxy terminus (denoted “C”) islocalized to the intracellular environment. In contrast, the type IImembrane protein of the right panel is characterized by an extracellularfacing carboxy terminus and an amino terminus in the intracellularspace.

FIG. 2 shows immune inhibitory and immune stimulatory signaling that isrelevant to the present invention (from Mahoney, Nature Reviews DrugDiscovery 2015:14; 561-585).

FIG. 3A shows a schematic illustration of how a type I and type IImembrane protein may be engineered with transmembrane and intracellulardomains removed (FIG. 3B) and adjoined using a linker sequence (FIG. 3C)to generate a single fusion protein wherein the extracellular domains ofthe type I and type II membrane proteins each face outward in a singlefusion protein (FIG. 3D). FIG. 3C depicts the linkage of a type I andtype II membrane protein by removal of the transmembrane andintracellular domains of each protein, and where the liberatedextracellular domains (ECD) from each protein have been adjoined by alinker sequence. The ECD in this depiction may include the entire aminoacid sequence of a candidate type I or type II protein which istypically localized outside the cell membrane, or any portion thereofwhich retains binding to the intended receptor or ligand. FIG. 3Ddepicts adjoined extracellular domains in a linear construct wherein theextracellular domain of the type I membrane protein faces the ‘left’side of the construct and the extracellular domain of the type IImembrane protein faces the “right” side of the construct.

FIG. 4A shows that tumor cells may express PD-L1 on the cell surface,which can bind to PD-1 expressed by a T cell (FIG. 4B). This interactionsuppresses activation of T cells. A fusion protein of the extracellulardomain of PD-1, adjoined to the extracellular domain of OX40L may bindto PD-L1 on the surface of a tumor cell, preventing binding to PD-1 onthe surface of a T cell (FIG. 4C). The fusion protein may then ‘dangle’from the surface of the tumor cell, and the OX40L portion of the fusionprotein may then bind to OX40 expressed on the surface of the T cell.This would result in replacement of an inhibitory PD-L1 signal with aco-stimulatory OX40L signal to enhance the anti-tumor activity of Tcells.

FIG. 5 shows the expression of chimeric mouse (m) PD-1-Fc andPD-1-Fc-OX40 ligand (L) from CHO-K1 cells detected using a mouse IgGcapture and anti-mIgG detection ELISA assay.

FIG. 6A and FIG. 6B show results from an ELISA assay confirming thebinding of mPD-1-Fc-OX40L to mOX40. FIG. 6A shows a schematicrepresentation of the ELISA method used to detect binding ofmPD-1-Fc-OX40L to mOX40. Recombinant mOX40 fused to human Fc (mOX40-hFc)was used to capture mPD-1-Fc-OX40L in the culture media. A rabbitpolyclonal antibody to mPD-1 was used to detect the mPD-1 domain in thechimeric protein and subsequently detected using a horseradishperoxidase (HRP)-conjugated polyclonal antibody to rabbit IgG (H+L).FIG. 6B shows results in which two-fold serial dilutions of the CHO-K1culture media containing mPD-1-Fc-OX40L protein was incubated withplate-bound mOX40-hFc and binding was measured by absorbance at 450 nm.mPD-1-Fc protein (which is not predicted to bind recombinant mouse OX40)containing culture media, as well as culture media alone, were used asnegative controls.

FIG. 7A and FIG. 7B show shows results from an ELISA assay confirmingbinding of mPD-1-Fc-OX40L to mPD-L1. FIG. 7A shows a schematicrepresentation of the ELISA method used to detect binding ofmPD-1-Fc-OX40L to mPD-L1. Recombinant mPD-L1 fused to human Fc(mPD-L1-hFc) was used to capture the mPD-1-Fc-OX40L chimeric protein inthe culture media. A horseradish peroxidase (HRP)-conjugated polyclonalantibody to mouse IgG (H+L) was used for the detection of the boundproteins. FIG. 7A shows results in which two-fold serial dilutions ofCHO-K1 culture media containing mPD-1-Fc-OX40L protein was incubatedwith plate-bound mPD-L1-hFc and binding was measured by absorbance at450 nm. mPD-1-Fc protein containing culture media was used as a positivecontrol and media alone was used as a negative control.

FIG. 8 shows that the in vivo intratumoral delivery of plasmid DNAencoding mouse (m) PD-1-Fc-OX40L led to an expansion of antigen-specificCD8+ T-cells. “EP only” is an electroporation negative control. In thisexperiment, C57BL/6 mice were adoptively transferred withovalbumin-specific CD8+ T cells (OT-I) 2 days before tumor inoculation.B16-F10-ova tumors were then implanted on the hind flank of each mouseon day 0.7-day established B16-F10-ova tumors were injected with theplasmid DNA encoding mPD1-Fc-OX40L and electroporated immediatelythereafter on days 7 and 10, as compared to the EP only control. Thefrequency of OT-1 cells was measured on the indicated days in theperipheral blood by flow cytometry.

FIG. 9 shows that the in vivo intratumoral delivery of plasmid DNAencoding mPD-1-Fc-OX40L led to tumor regression in the B16.F10-ovamelanoma tumor model. “EP only” is an electroporation negative control.Mice were treated as indicated in FIG. 9, and the tumor diameter wasmeasured on the indicated days.

FIG. 10A to FIG. 10F show results from additional characterization ofmPD-1-Fc-OX40L. FIG. 10A provides Western blot analysis probed withantibodies for mPD-1 (left gel), mFc (middle gel) and mOX40L (rightgel), run in reducing or non-reducing condition and with or without thedeglycosylase PNGase F (as indicated by the ‘+’ or ‘−’ marks above eachblot). The murine protein has a predicted molecular weight of ˜60 kDa asa monomeric protein. FIG. 10B shows results from a functional ELISAassay demonstrating the binding of mPD-1-Fc-OX40L to mPD-L1 and mOX40.For each set of histograms, the bars represent, from left to right, aserial dilution of the purified mPD1-Fc-OX40L fusion protein. FIG. 10Cshows results from a functional ELISA assay demonstrating the binding ofmPD-1-Fc-OX40L to mFc (for each concentration, OX40-His is the left barand HVEM-His is the right bar). FIG. 10D shows binding to mPD-1-Fc-OX40Lto activated mouse splenocytes as detected on HLA I-A/I-E⁺PD-L1⁺(APC⁺PD-L1⁺) and CD4⁺OX40⁺ cells (for each graph, the cell populationsto the left represent APC-PD-L1⁻ or CD4⁻OX40⁻ cells and the cellpopulations to the right represent APC⁺PD-L1⁺ or CD4⁺OX40⁺ cells). FIG.10E shows identification of PD-L1_(low) (4T1) and PD-L1_(high)(B16.F10)cell lines. FIG. 10F shows results from a splenocyte/tumor co-cultureassay. IL2 ELISA was performed 5 days after initial harvest. The linegraphs from left to right represent +4T1 cells (−FP), +4T1 cells (+500ng FP), +4T1 cells (+5 ug FP), +B16 cells (−FP), +B16 cells (+500 ngFP), and +B16 cells (+5 ug FP).

FIG. 11A to FIG. 11L show the anti-tumor efficacy of mPD-1-Fc-OX40L.FIG. 11A shows MC38 tumor growth kinetics following treatment with theindicated regimens. Balb.c mice were inoculated in the hind flank with2.5×10⁵ MC38-ova tumor cells. On days 5 and 8, mice were treated withthe indicated treatment group. Anti-OX40 treated animals received 100 μgof OX86 mAb on each of two days, anti-PD-L1 treated animals received 100μg of 10F.9G2 mAb on each of two days, anti-OX40 and anti-PD-L1combination treated animals received 100 μg each of OX86 and 10F.9G2 oneach of two days and mPD1-Fc-OX40L treated mice received 100 μg total ofmPD1-Fc-OX40L on each of two days. Tumor area was calculated on theindicated days by taking perpendicular tumor diameter meaurements usingelectronic calipers. On day 40, mice which had completely rejected theprior tumor (no visible or palpable tumor remained), were challengedwith 2.5×10⁵ MC38 parental (not expressing ova) tumor cells, without anyadditional treatment, and tumor area was calculated as stated above.FIG. 11B shows the overall survival for each treatment group over thecourse of the experiment as determined by overall tumor size exceeding150 mm² according to IACUC protocols (at day 65, the curves are, top tobottom, αOX40/αPD-L1, mPD1-Fc-OX40L, αOX40, αPD-L1, and untreated). FIG.11C shows peripheral blood analysis of CD4/CD8 ratio (top) and thepercentage of FOXP3+ Treg cells (bottom) for each indicated treatmentgroup (in both graphs, the treatment groups are, lefft to right,untreated, αOX40, αPD-L1, αOX40/αPD-L1, and mPD1-Fc-OX40L). FIG. 11Dshows serum cytokine analysis of IFNγ, TNFα, IL4, and IL6. For each setof data, the line graphs from left to right represent untreated, α-OX40,α-PD-L1, α-OX40/α-PD-L1, and mPD-1-Fc-OX40L (in the four graphs, thetreatment groups are, left to right, untreated, αOX40, αPD-L1,αOX40/αPD-L1, and mPD1-Fc-OX40L). FIG. 11E shows the mean tumor size foreach treatment group on day 13 of the experiment (for each grapgh, thesamples are, left to right: untreated, mPD1-Fc-OX40L, mPD1-Fc-GITRL,mCD172a-Fc-CD40L, αOX40, αPD-L1, and a GITR). FIG. 11F shows thepercentage of KSP Tetramer specific CD8+ T cells isolated from the tumor(TIL) for each treatment group on day 13 of the experiment (for eachgrapgh, the samples are, left to right: untreated, mPD1-Fc-OX40L,mPD1-Fc-GITRL, mCD172a-Fc-CD40L, αOX40, αPD-L1, and a GITR). FIG. 11Gshows the phenotype of CD8+ splenocytes according to well characterized‘immune memory’ markers on day 13 of the experiment for each treatmentgroup (for each grapgh, the samples are, left to right: untreated,mPD1-Fc-OX40L, mPD1-Fc-GITRL, mCD172a-Fc-CD40L, αOX40, αPD-L1, and aGITR). FIG. 11H shows the ratio of CD4 to CD8 cells in the peripheralblood (left panel), spleen (middle panel) and tumor (right panel) foreach treatment group on day 13 of the experiment (for each grapgh, thesamples are, left to right: untreated, mPD1-Fc-OX40L, mPD1-Fc-GITRL,mCD172a-Fc-CD40L, αOX40, αPD-L1, and a GITR). FIG. 11I shows a schematicfor how each animal was treated in each experiment using the CT26 colontumor model. FIG. 11J provides representative flow cytometry plots usedto calculate the serum concentration of each indicated serum cytokineusing the Legend Plex bead array kit from BioLegend. Each indicatedcytokine included in the panel is indicated, and the mean-fluorescenceintensity of each bead cluster is used to calculate the relativeconcentration of each cytokine in the serum. FIG. 11K provides anexample for how the Legend Plex assay can be used as a pharmacodynamicbiomarker of dose response for the PD1-Fc-OX40L fusion protein. Usingthe concentration of IFNγ as an example, increasing concentrations ofthis cytokine are shown to correspond with increasing treatment amountsof PD1-Fc-OX40L (FIG. 11K shows, left to right, untreated, 40 ug×1, 40ug×2, 100 ug×1, and 100 ug×2). FIG. 11L shows CT26 tumor growth kineticsfor each treatment group.

FIG. 12A shows the predicted tertiary structure of human PD-1-Fc-OX40Las determined by RaptorX. FIG. 12B shows immunogenicity assessment ofhuman PD-1-Fc-OX40 using iTope, an in si/lico modeling algorithm(ANTITOPE/ABZENA), cross referenced to a proprietary T cell epitopedatabase.

FIG. 13A to FIG. 13D show characterization of human PD-1-Fc-OX40L (alsoreferred to as SL-279252). FIG. 13A shows protein A elution peaks(OD450) from SL-279252 purified from stable (in-house) and or transienttransfection (Thermo) preparations. ELISA results from each elution peakare overlayed on the absorbance readings to indicate that the SL279252protein is contained within the first elution peak from the column. FIG.13B shows Western blot analysis of SL-279252, performed by probingpurified protein with human anti-PD-1 (left gel), anti-Fc (middle gel),and anti-OX40L (right gel) antibodies, under non-reducing and reducingconditions, and with or without the deglycosylase PNGase F. Thepredicted molecular weight of monomeric SL-279252 is 60.3 kDa. FIG. 13Cshows results from functional ELISAs using capturing with recombinanthOX40 and detection with Gt-hOX40L/Gt-HRP as compared to a recombinanthuman OX40L-Fc standard. FIG. 13D shows results from functional ELISAsdesigned to test functional binding for each side of SL-279252simultaneously. Specifically, recombinant human PD-L1 was absorbed to aplate and used to capture SL-279252. Captured protein was then detectedusing recombinant hOX40-his/HRP rabbit anti-his versus HVEM-his as anegative control for specificity.

FIG. 14A to FIG. 14O show surface plasmon resonance (SPR) and half-lifeanalysis of SL-279252. The ‘on-rate (Ka)’, ‘off-rate (Kd)’, and bindingaffinity (K_(D)) were determined for SL-279252, when binding to humanPD-L1 (FIG. 14A), human PD-L2 (FIG. 14B), human OX40 (FIG. 14C), humanFcγR1A (FIG. 14D), and FcRn (FIG. 14E), compared with the appropriatecontrols. FIG. 14F summarizes the on-rate (Ka), off rate (Kd), andbinding affinity (KD) for each condition tested. The binding of amodified SL-279252 construct containing a distinct leader peptide aswell as mutations in the Fc region to increase binding to FcRn was alsotested when binding to human PD-L1 (FIG. 14G), human PD-L2 (FIG. 14H),human OX40 (FIG. 14I), human FcγR1A (FIG. 14J), and FcRn (FIG. 14K),compared with the appropriate controls. FIG. 14L summarizes the on-rate(Ka), off rate (Kd), and binding affinity (KD) for each conditiontested. FIG. 14M shows the in vivo serum half-life of SL-279252 inC57BL/6 mice. FIG. 14N shows the in vivo intra-tumoral half-life ofSL-279252 in immunocompromised (NSG) mice that were implanted with humanPD-L1 positive tumor on on flank (HeLa-PD-L1) and PD-L1 negative tumoron the opposite flank (HeLa). On the indicated days, the two tumors wereexcised and bi-sected. Half of the bisected tumor was disaggregated andtested for SL-279252 binding by flow cytometry using antibodies againsthuman OX40L. FIG. 14O shows frozen sections from the other half of thebisected tumors 6 hours, 2 days and 5 days after treatment with a singleinjection of SL-279252. The figure indicates persistence of SL-279252 atleast 5 days following administration.

FIG. 15A to FIG. 15J show binding of SL-279252 to cells in vitro. InFIG. 15A, parental Jurkat (cell population to the left) and Jurkat/hOX40(cell population to the right) cells were assessed by flow cytometryusing a hOX40-APC antibody. In FIG. 15B, parental CHO-K1 cells (cellpopulation to the left) and CHO-K1/hPD-L1 (cell population to the right)were assessed by flow cytometry using a hPD-L1-APC antibody. In FIG.15C, parental CHO-K1 cells (cell population to the left) andCHO-K1/hCD47 (cell population to the right) were assessed by flowcytometry using a hCD47-APC antibody. In FIG. 15D, increasingconcentrations of SL-279252 were incubated with parental CHO-K1 cells(left panel) and CHO-K1/hPD-L1 (middle panel) and detected withanti-human OX40L-APC antibody. The right panel shows the titration curvefor increasing concentrations of SL-279252. In FIG. 15E, increasingconcentrations of SL-279252 were incubated with parental Jurkat cells(left panel) or Jurkat/hOX40 cells (middle panel) and detected withanti-human OX40L-APC antibody. The right panel shows the titration curvefor increasing concentrations of SL-279252. In FIG. 15F, increasingconcentrations of hCD172a-Fc-OX40L were incubated with parental CHO-K1cells (left panel) or CHO-K1-CD47 cells (middle panel) and detected withan anti-human OX40L-APC antibody. The right panel shows the titrationcurve for increasing concentrations of hCD172a-Fc-OX40L. FIG. 15G showsbinding of increasing concentrations of hCD172a-Fc-OX40L to parentalJurkat cells (left panel) or Jurkat-hOX40 cells (middle panel). Theright panel shows the titration curve for increasing concentrations ofhCD172a-Fc-OX40L. In FIG. 15H, human PD-L1₁₀ (PC3 cells; cell populationto the left) and PD-L1_(high) (HCC827; cell population to the right)were identified by flow cytometry. In FIG. 15I, increasingconcentrations of SL-279252 were incubated with PC3 cells. In FIG. 15J,increasing concentrations of SL-279252 were incubated with HCC827 cellsfor 2 hours. Cells were washed and analyzed by flow cytometry forSL-279252 binding (Fc-PE antibody).

FIG. 16A to FIG. 16E show the ex vivo functional characterization ofSL-279252. In FIG. 16A, OX40 expression was detected in human T cellsisolated from PBMCs treated for 2 days with PMA/PHA/lonomycin (Ion.). InFIG. 16B, binding of SL-279252 was assessed in activated CD4+ and CD8+cells (Fc-PE secondary). FIG. 16C provides a schematic representation ofa T cell/tumor co-culture assay to detect T cell activation as well as atime-line for the experiment. In FIG. 16D, co-culture media was assessedby IL2 ELISA 6 days after initial T cell isolation. The line graphs,from left to right, represent+PC3 (−FP), +PC3 (+500 ng FP), +PC3 (+5 ugFP), +HCC827 (−FP), +HCC827 (+500 ng FP), and +HCC827 (+5 ug FP). InFIG. 16E, co-cultured T cells were analyzed by flow cytometry 5 daysafter initial isolation for proliferation of CD4+ and CD8+ cells (Ki67)and 7 days after isolation for cytokine expression in CD8+ cells. Theline graphs, from left to right, represent+HCC827 (−FP), +HCC827 (+500ng FP), and +HCC827 (+5 ug FP).

FIG. 17A shows Western blot analysis of various chimeric proteinsincluding hCD172a-Fc-OX40L, hPD1-Fc-TL1A, hBTLA-Fc-OX40L,hTMIGD2-Fc-OX40L, hTIM3-Fc-OX40L, mPD1-Fc-GITRL, mPD1-Fc-4-1BBL,mPD1-Fc-TL1A, mCD172a-Fc-CD40L. Each chimeric protein was probed withantibodies specific for each binding end and the central Fc domain.ELISA assays were performed to confirm binding of various chimericproteins to human OX40. FIG. 17B shows a schematic representation of theELISA method used to detect binding of chimeric proteins to human OX40.FIG. 17C shows results of human PD1-Fc-OX40L binding to parental Jurkatcells (left panel, left curve) or to Jurkat/OX40 cells (left panel,right curve). Two negative controls were used to demonstratespecificity: human PD1-Fc-TL1A (middle panel) and canine PD1-Fc-OX40L(right panel). FIG. 17D shows the predicted tertiary structure of ahuman CD172a-Fc-OX40L as determined by RaptorX. FIG. 17E shows anexample production and purification of human PD1-Fc-OX40L (SL-279252)including the Coomassie-Gel (upper left), anti-IgG Western blot (upperright), eluted protein concentration (lower left) and elution profilefrom affinity chromatography (lower right). FIG. 17F shows an exampleproduction and purification of human CD172a-Fc-OX40L including theCoomassie-Gel (upper left), anti-IgG Western blot (upper right), elutedprotein concentration (lower left) and elution profile from affinitychromatography (lower right). FIG. 17G shows an example production andpurification of mouse CD172a-Fc-CD40L including the purificationparameters (upper table) and the LabChip purified protein analysis(lower panel). FIG. 17H shows an example production and purification ofhuman TIGIT-Fc-OX40L including the Coomassie-Gel (upper left), anti-IgGWestern blot (upper right), eluted protein concentration (lower left)and elution profile from affinity chromatography (lower right). FIG. 17Ishows the binding affinity of human CD172a-Fc-OX40L to immobilizedrecombinant CD47. FIG. 17J shows the binding affinity of humanCD172a-Fc-OX40L to immobilized recombinant human OX40. FIG. 17K showsthe binding affinity of human CD172a-Fc-OX40L to immobilized recombinanthuman FcγR1A. FIG. 17L shows the binding affinity of humanCD172a-Fc-OX40L to immobilized recombinant human FcRn. FIG. 17M shows asummary of the on-rate (Ka), off-rate (Kd), and binding affinity (KD)for each condition tested. FIG. 17N shows an example production andpurification of canine PD1-Fc-OX40L including the Coomassie-Gel (upperleft), anti-IgG Western blot (upper right), eluted protein concentration(lower left) and elution profile from affinity chromatography (lowerright). FIG. 17O shows an example production and purification of mousePD1-Fc-OX40L including the Coomassie-Gel (upper left), anti-IgG Westernblot (upper right), eluted protein concentration (lower left) andelution profile from affinity chromatography (lower right). FIG. 17Pshows an example production and purification of mouse PD1-Fc-GITRLincluding the Coomassie-Gel (upper left), anti-IgG Western blot (upperright), eluted protein concentration (lower left) and elution profilefrom affinity chromatography (lower right). FIG. 17Q shows an exampleproduction and purification of mouse PD1-Fc-41BBL including theCoomassie-Gel (upper left), anti-IgG Western blot (upper right), elutedprotein concentration (lower left) and elution profile from affinitychromatography (lower right). FIG. 17R shows an example production andpurification of mouse PD1-Fc-TL1A including the Coomassie-Gel (upperleft), anti-IgG Western blot (upper right), eluted protein concentration(lower left) and elution profile from affinity chromatography (lowerright). FIG. 17S shows an example production and purification of mouseCD115-Fc-CD40L including the Coomassie-Gel (upper left), anti-IgGWestern blot (upper right), eluted protein concentration (lower left)and elution profile from affinity chromatography (lower right). FIG. 17Tshows an example production and purification of human PD1-Fc-GITRLincluding the Coomassie-Gel (upper left), anti-IgG Western blot (upperright), eluted protein concentration (lower left) and elution profilefrom affinity chromatography (lower right).

DETAILED DESCRIPTION

The present invention is based, in part, on the discovery that chimericproteins can be engineered from the extracellular, or effector, regionsof immune-modulating transmembrane proteins in a manner that exploitsthe orientations of these proteins (e.g. type I versus type II) andtherefore allows the delivery of immune stimulatory and/or immuneinhibitory signals, including, for example, masking an immune inhibitorysignal and replacing it with an immune stimulatory signal in thetreatment of cancer.

Chimeric Proteins

In one aspect, the present invention relates to a chimeric proteincomprising: (a) a first extracellular domain of a type I transmembraneprotein at or near the N-terminus, (b) a second extracellular domain ofa type II transmembrane protein at or near the C-terminus, and (c) alinker, wherein one of the first and second extracellular domains is animmune inhibitory signal and one of the first and second extracellulardomains is an immune stimulatory signal.

In some embodiments, chimeric protein refers to a recombinant fusionprotein, e.g. a single polypeptide having the extracellular domainsdescribed herein (and, optionally a linker). For example, in variousembodiments, the chimeric protein is translated as a single unit in acell. In some embodiments, chimeric protein refers to a recombinantprotein of multiple polypeptides, e.g. multiple extracellular domainsdescribed herein, that are linked to yield a single unit, e.g. in vitro(e.g. with one or more synthetic linkers described herein).

In some embodiments, an extracellular domain refers to a portion of atransmembrane protein which is capable of interacting with theextracellular environment. In various embodiments, an extracellulardomain refers to a portion of a transmembrane protein which issufficient to bind to a ligand or receptor and effective transmit asignal to a cell. In various embodiments, an extracellular domain is theentire amino acid sequence of a transmembrane protein which is externalof a cell or the cell membrane. In various embodiments, an extracellulardomain is the that portion of an amino acid sequence of a transmembraneprotein which is external of a cell or the cell membrane and is neededfor signal transduction and/or ligand binding as may be assayed usingmethods know in the art (e.g. in vitro ligand binding and/or cellularactivation assays).

In some embodiments, an immune inhibitory signal refers to a signal thatdiminishes or eliminates an immune response. For example, in the contextof oncology, such signals may diminish or eliminate antitumor immunity.Under normal physiological conditions, inhibitory signal are useful inthe maintenance of self-tolerance (e.g. prevention of autoimmunity) andalso to protect tissues from damage when the immune system is respondingto pathogenic infection. For instance, without limitation, immuneinhibitory signal may be identified by detecting an increase in cellularproliferation, cytokine production, cell killing activity or phagocyticactivity when such an inhibitory signal is blocked. Specific examplessuch inhibitory signals include blockade of PD-1 of PD-L1/L2 usingantibody mediated blockade or through competitive inhibition of PD-L1/L2using PD-1 containing fusion proteins. When such an inhibitory signal isblocked through inhibition of PD-L1/L2, it leads to enhance tumorkilling activity by T cells because they are no longer being inhibitedby PD-L1 or PD-L2. In another example, and inhibitory signal may beprovided by CD47 to macrophages expressing CD172a. Binding of CD47 toCD172a typically inhibits the ability of a macrophage to phagocytose atarget cell, which can be restored through blockade of CD47 withblocking antibodies or through competitive inhibition of CD47 usingCD172a containing fusion proteins.

In some embodiments, an immune stimulatory signal refers to a signalthat enhances an immune response. For example, in the context ofoncology, such signals may enhance antitumor immunity. For instance,without limitation, immune stimulatory signal may be identified bydirectly stimulating proliferation, cytokine production, killingactivity or phagocytic activity of leukocytes. Specific examples includedirect stimulation of TNF superfamily receptors such as OX40, 4-1BB orTNFRSF25 using either receptor agonist antibodies or using fusionproteins encoding the ligands for such receptors (OX40L, 4-1BBL, TL1A,respectively). Stimulation from any one of these receptors may directlystimulate the proliferation and cytokine production of individual T cellsubsets. Another example includes direct stimulation of an immuneinhibitory cell with through a receptor that inhibits the activity ofsuch an immune suppressor cell. This would include, for example,stimulation of CD4+FoxP3+ regulatory T cells with a GITR agonistantibody or GITRL containing fusion protein, which would reduce theability of those regulatory T cells to suppress the proliferation ofconventional CD4+ or CD8+ T cells. In another example, this wouldinclude stimulation of CD40 on the surface of an antigen presenting cellusing a CD40 agonist antibody or a fusion protein containing CD40L,causing activation of antigen presenting cells including enhancedability of those cells to present antigen in the context of appropriatenative costimulatory molecules, including those in the B7 or TNFsuperfamily.

Membrane proteins typically consist of an extracellular domain, one or aseries of trans-membrane domains, and an intracellular domain. Withoutwishing to be bound by theory, the extracellular domain of a membraneprotein is responsible for interacting with a soluble or membrane boundreceptor or ligand. Without wishing to be bound by theory, thetrans-membrane domain(s) are responsible for localizing a protein to theplasma membrane. Without wishing to be bound by theory, theintracellular domain of a membrane protein is responsible forcoordinating interactions with cellular signaling molecules tocoordinate intracellular responses with the extracellular environment(or visa-versa). There are two types of single-pass membrane proteins,those with an extracellular amino terminus and intracellular carboxyterminus (type I) and those with an extracellular carboxy terminus andintracellular amino terminus (type II). Both type I and type II membraneproteins can be either receptors or ligands. For type I membraneproteins, the amino terminus of the protein faces outside the cell, andtherefore contains the functional domains that are responsible forinteracting with other binding partners (either ligands or receptors) inthe extracellular environment (FIG. 1, left image). For type II membraneproteins, the carboxy terminus of the protein faces outside the cell,and therefore contains the functional domains that are responsible forinteracting with other binding partners (either ligands or receptors) inthe extracellular environment (FIG. 1, right image). Thus, these twotypes of proteins have opposite orientations to each other.

Because the outward facing domains of type I and type II membraneproteins are opposite (FIG. 1), it is possible to link the extracellulardomains of a type I and type II membrane protein such that the ‘outwardfacing’ domains of the molecules are also in opposing orientation toeach other (FIG. 3). The resulting construct would therefore consist ofthe extracellular domain of a type I membrane protein on the ‘left’ sideof the molecule, connected to the extracellular domain of a type IImembrane protein on the ‘right’ side of the molecule using a linkersequence. This construct could be produced by cloning of these threefragments (the extracellular domain of a type I protein, followed by alinker sequence, followed by the extracellular domain of a type IIprotein) into a vector (plasmid, viral or other) wherein the aminoterminus of the complete sequence corresponded to the ‘left’ side of themolecule containing the type I protein and the carboxy terminus of thecomplete sequence corresponded to the ‘right’ side of the moleculecontaining the type II protein. Accordingly, in various embodiments, thepresent chimeric proteins are engineered as such.

In some embodiments, the extracellular domain may be used to produce asoluble protein to competitively inhibit signaling by that receptor'sligand. In some embodiments, the extracellular domain may be used toprovide artificial signaling.

In some embodiments, the extracellular domain of a type I transmembraneprotein is an immune inhibitory signal. In some embodiments, theextracellular domain of a type II transmembrane protein is an immunestimulatory signal.

In some embodiments, the present chimeric proteins comprise anextracellular domain of a type I transmembrane protein, or a functionalfragment thereof. In some embodiments, the present chimeric proteinscomprise an extracellular domain of a type II transmembrane protein, ora functional fragment thereof. In some embodiments, the present chimericproteins comprise an extracellular domain of a type I transmembraneprotein, or a functional fragment thereof, and an extracellular domainof a type II transmembrane protein, or a functional fragment thereof.

In various embodiments, the present chimeric proteins comprise anextracellular domain of a human type I transmembrane protein as recitedin TABLE 1, or a functional fragment thereof. In various embodiments,the present chimeric proteins comprise an extracellular domain of ahuman type II transmembrane protein as recited in TABLE 2, or afunctional fragment thereof. In some embodiments, the present chimericproteins comprise an extracellular domain of a type I transmembraneprotein as recited in TABLE 1, or a functional fragment thereof, and anextracellular domain of a type II transmembrane protein as recited inTABLE 2, or a functional fragment thereof. TABLEs 1 and 2 are providedelsewhere herein.

In various embodiments, the present chimeric proteins may be engineeredto target one or more molecules that reside on human leukocytesincluding, without limitation, the extracellular domains (whereapplicable) of SLAMF4, IL-2 R α, 4-1BB/TNFRSF9, IL-2 R β, ALCAM, B7-1,IL-4 R, B7-H3, BLAME/SLAMFS, CEACAM1, IL-6 R, IL-7 Rα, IL-10R α, IL-I 0R β, IL-12 R β1, IL-12 R β2, CD2, IL-13 R α 1, IL-13, CD3, CD4,ILT2/CDS5j, ILT3/CDS5k, ILT4/CDS5d, ILT5/CDS5a, lutegrin α 4/CD49d, CDS,Integrin α E/CD103, CD6, Integrin α M/CD11 b, CDS, Integrin a X/CD11c,Integrin β 2/CDIS, KIR/CD15S, CD27/TNFRSF7, KIR2DL1, CD2S, KIR2DL3,CD30/TNFRSFS, KIR2DL4/CD15Sd, CD31/PECAM-1, KIR2DS4, CD40 Ligand/TNFSF5,LAG-3, CD43, LAIR1, CD45, LAIR2, CDS3, Leukotriene B4-R1, CDS4/SLAMF5,NCAM-L1, CD94, NKG2A, CD97, NKG2C, CD229/SLAMF3, NKG2D, CD2F-10/SLAMF9,NT-4, CD69, NTB-A/SLAMF6, Common γ Chain/IL-2 R γ, Osteopontin,CRACC/SLAMF7, PD-1, CRTAM, PSGL-1, CTLA-4, RANK/TNFRSF11A, CX3CR1,CX3CL1, L-Selectin, SIRP β 1, SLAM, TCCR/WSX-1, DNAM-1, Thymopoietin,EMMPRIN/CD147, TIM-1, EphB6, TIM-2, Fas/TNFRSF6, TIM-3, FasLigand/TNFSF6, TIM-4, Fcγ RIII/CD16, TIM-6, TNFR1/TNFRSF1A, Granulysin,TNF RIII/TNFRSF1B, TRAIL RI/TNFRSFIOA, ICAM-1/CD54, TRAIL R2/TNFRSF10B,ICAM-2/CD102, TRAILR3/TNFRSF10C, IFN-γR1, TRAILR4/TNFRSF10D, IFN-γ R2,TSLP, IL-1 R1 and TSLP R.

The activation of regulatory T cells is critically influenced bycostimulatory and coinhibitory signals. Two major families ofcostimulatory molecules include the B7 and the tumor necrosis factor(TNF) families. These molecules bind to receptors on T cells belongingto the CD28 or TNF receptor families, respectively. Many well-definedcoinhibitors and their receptors belong to the B7 and CD28 families.

In various embodiments, the present chimeric proteins may be engineeredto target one or more molecules involved in immune inhibition, includingfor example: CTLA-4, PD-L1, PD-L2, PD-1, BTLA, HVEM, TIM3, GAL9, LAG3,VISTA/VSIG8, KIR, 2B4, TIGIT, CD160 (also referred to as BY55), CHK 1and CHK2 kinases, A2aR, CEACAM (e.g., CEACAM-1, CEACAM-3 and/orCEACAM-5), and various B-7 family ligands (including, but are notlimited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6and B7-H7).

In various embodiments, the chimeric protein of the present inventioncomprises an extracellular domain of an immune inhibitory agent,including without limitation, one or more of TIM-3, BTLA, PD-1, CTLA-4,CD244, CD160, TIGIT, SIRPa/CD172a, 2B4, VISTA, VSIG8, LAG3, CD200 andTMIGD2.

In some embodiments, the chimeric protein of the present inventioncomprises an extracellular domain of a type I membrane protein which hasimmune inhibitory properties. In various embodiments, the chimericprotein is engineered to disrupt, block, reduce, and/or inhibit thetransmission of an immune inhibitory signal, by way of non-limitingexample, the binding of PD-1 with PD-L1 or PD-L2 and/or the binding ofCD172a with CD47 and/or the binding of TIM-3 with galectin-9 and/orphosphatidyserine.

In some embodiments, the chimeric protein of the present inventioncomprises an extracellular domain of an immune stimulatory signal is oneor more of OX-40 ligand (OX-40L), LIGHT (CD258), GITR ligand (GITRL),CD70, CD30 ligand, CD40 ligand (CD40L), CD137 ligand, TRAIL, and TL1A.

In various embodiments, the chimeric protein simulates binding of aninhibitory signal ligand to its cognate receptor (e.g. PD-1 to PD-L1 orPD-L2; e.g. CD172a to CD47; e.g. CD115 to CSF1; e.g. TIM-3 to galectin-9or phosphatidylserine) but inhibits the inhibitory signal transmissionto an immune cell (e.g. a T cell, macrophage or other leukocyte).

In various embodiments, the chimeric protein comprises an immuneinhibitory receptor extracellular domain and an immune stimulatoryligand extracellular domain which can, without limitation, deliver animmune stimulation to a T cell while masking a tumor cell's immuneinhibitory signals. In various embodiments, the chimeric proteindelivers a signal that has the net result of T cell activation.

In some embodiments, the chimeric protein comprises an immune inhibitorysignal which is an ECD of a receptor of an immune inhibitory signal andthis acts on a tumor cell that bears a cognate ligand of the immuneinhibitory signal. In some embodiments, the chimeric protein comprisesan immune stimulatory signal which is an ECD of a ligand of an immunestimulatory signal and this acts on a T cell that bears a cognatereceptor of the immune stimulatory signal. In some embodiments, thechimeric protein comprises both (i) an immune inhibitory signal which isa receptor of an immune inhibitory signal and this acts on a tumor cellthat bears a cognate ligand of the immune inhibitory signal and (ii) animmune stimulatory signal which is a ligand of an immune stimulatorysignal and this acts on a T cell that bears a cognate receptor of theimmune stimulatory signal.

In some embodiments, the chimeric protein of the present inventioncomprises an extracellular domain of one or more of theimmune-modulating agents described in Mahoney, Nature Reviews DrugDiscovery 2015:14; 561-585, the entire contents of which are herebyincorporated by reference. For example, with reference to present FIG.2, the chimeric protein bears an immune inhibitory signal (denoted by“−”) which is a receptor of the pair (i.e. right side of the figure) andthe tumor cell bears a ligand selected from the left side of the figure.By way of further example, with reference to present FIG. 2, thechimeric protein bears an immune stimulatory signal (denoted by “+”)which is a ligand of the pair (i.e. left side of the figure) and thetumor cell bears a receptor selected from the right side of the figure.

In some embodiments, the chimeric protein of the present inventioncomprises an extracellular domain of a type II membrane protein whichhas immune stimulatory properties. In various embodiments, the chimericprotein is engineered to enhance, increase, and/or stimulate thetransmission of an immune stimulatory signal, by way of non-limitingexample, the binding of GITR with one or more of GITR ligand and/or thebinding of OX40 with OX40L and/or the binding of CD40 with CD40 ligand.

In some embodiments, the chimeric protein comprises the extracellulardomain of the immune inhibitory agent PD-1 and is paired with an immunestimulatory agent as follows: PD-1/4-1BBL; PD-1/OX-40L; PD-1/LIGHT;PD-1/GITRL; PD-1/CD70; PD-1/CD30L; PD-1/CD40L; and PD-1/TL1A.

In an embodiment, the chimeric protein comprises the extracellulardomain of the immune inhibitory agent PD-1 and is paired with the immunestimulatory agent OX-40L. In an embodiment, the chimeric proteincomprises the amino acid sequence of SEQ ID NO: 22. In variousembodiments, the chimeric protein binds to human PD-L1 or PD-L2 with aK_(D) of about 1 nM to about 5 nM, for example, about 1 nM, about 1.5nM, about 2 nM, about 2.5 nM, about 3 nM, about 3.5 nM, about 4 nM,about 4.5 nM, or about 5 nM. In various embodiments, the chimericprotein binds to human PD-L1 with a K_(D) of about 5 nM to about 15 nM,for example, about 5 nM, about 5.5 nM, about 6 nM, about 6.5 nM, about 7nM, about 7.5 nM, about 8 nM, about 8.5 nM, about 9 nM, about 9.5 nM,about 10 nM, about 10.5 nM, about 11 nM, about 11.5 nM, about 12 nM,about 12.5 nM, about 13 nM, about 13.5 nM, about 14 nM, about 14.5 nM,or about 15 nM.

In various embodiments, the chimeric protein exhibits enhanced stabilityand protein half-life. In some embodiments, the chimeric protein bindsto FcRn with high affinity. In various embodiments, the chimeric proteinmay bind to FcRn with a K_(D) of about 70 nM to about 80 nM. Forexample, the chimeric protein may bind to FcRn with a K_(D) of about 70nM, about 71 nM, about 72 nM, about 73 nM, about 74 nM, about 75 nM,about 76 nM, about 77 nM, about 78 nM, about 79 nM, or about 80 nM. Insome embodiments, the chimeric protein does not substantially bind toother Fc receptors (i.e. other than FcRn) with effector function.

In some embodiments, the chimeric protein comprises the extracellulardomain of the immune inhibitory agent PD-L1 or PD-L2 and is paired withan immune stimulatory receptor as follows: PD-L1/4-1BB; PD-L1/OX-40;PD-L1/HVEM; PD-L1/GITR; PD-L1/CD27; PD-L1/CD28; PD-L1/CD30; PD-L1/CD40and PD-L1/CD137.

In some embodiments, the chimeric protein comprises the extracellulardomain of the immune inhibitory agent PD-L2 and is paired with an immunestimulatory receptor as follows: PD-L2/4-1BB; PD-L2/OX-40; PD-L2/HVEM;PD-L2/GITR; PD-L2/CD27; PD-L2/CD28; PD-L2/CD30; PD-L2/CD40 andPD-L2/CD137.

In some embodiments, the chimeric protein comprises the extracellulardomain of the immune inhibitory agent TIM-3 and is paired with an immunestimulatory agent as follows: TIM-3/OX-40L; TIM-3/LIGHT; TIM-3/GITRL;TIM-3/CD70; TIM-3/CD30L; TIM-3/CD40L; TIM-3/CD137L; TIM-3/TL1A; andTIM-3/OX40L.

In some embodiments, the chimeric protein comprises the extracellulardomain of the immune inhibitory agent BTLA and is paired with an immunestimulatory agent as follows: BTLA/OX-40L; BTLA/LIGHT; BTLA/GITRL;BTLA/CD70; BTLA/CD30L; BTLA/CD40L; BTLA/CD137L; BTLA/TL1A; andBTLA/OX40L.

In some embodiments, the chimeric protein comprises the extracellulardomain of the immune inhibitory agent CD172a/SIRPα and is paired with animmune stimulatory agent as follows: CD172a/OX-40L; CD172a/LIGHT;CD172a/CD70; CD172a/CD30L; CD172a/CD40L; CD172a/CD137L; CD172a/TL1A; andCD172a/OX40L.

In some embodiments, the chimeric protein comprises the extracellulardomain of the immune inhibitory agent CD115 and is paired with an immunestimulatory agent as follows: CD115/OX-40L; CD115/LIGHT; CD115/CD70;CD115/CD30L; CD115/CD40L; CD115/CD137L; CD115/TL1A; and CD115/OX40L.

In some embodiments, the chimeric protein comprises the extracellulardomain of the immune inhibitory agent TIGIT and is paired with an immunestimulatory agent as follows: TIGIT/OX-40L; TIGIT/LIGHT; TIGIT/GITRL;TIGIT/CD70; TIGIT/CD30L; TIGIT/CD40L; TIGIT/CD137L; TIGIT/TL1A; andTIGIT/OX40L.

In some embodiments, the chimeric protein comprises the extracellulardomain of the immune inhibitory agent TMIGD2 and is paired with animmune stimulatory agent as follows: TMIGD2/OX-40L; TMIGD2/LIGHT;TMIGD2/GITRL; TMIGD2/CD70; TMIGD2/CD30L; TMIGD2/CD40L; TMIGD2/CD137L;TMIGD2/TL1A; and TMIGD2/OX40L.

In some embodiments, the chimeric protein comprises the extracellulardomain of the immune inhibitory agent LAG3 and is paired with an immunestimulatory agent as follows: LAG3/OX-40L; LAG3/LIGHT; LAG3/GITRL;LAG3/CD70; LAG3/CD30L; LAG3/CD40L; LAG3/CD137L; LAG3/TL1A; andLAG3/OX40L.

In some embodiments, the chimeric protein comprises the extracellulardomain of the immune inhibitory agent VSIG8 and is paired with an immunestimulatory agent as follows: VSIG8/OX-40L; VSIG8/LIGHT; VSIG8/GITRL;VSIG8/CD70; VSIG8/CD30L; VSIG8/CD40L; VSIG8/CD137L; VSIG8/TL1A; andVSIG8/OX40L.

In some embodiments, the chimeric protein comprises the extracellulardomain of the immune inhibitory agent CD200 and is paired with an immunestimulatory agent as follows: CD200/OX-40L; CD200/LIGHT; CD200/GITRL;CD200/CD70; CD200/CD30L; CD200/CD40L; CD200/CD137L; CD200/TL1A; andCD200/OX40L.

In various embodiments, the present chimeric proteins may comprisesvariants of the extracellular domains described herein, for instance, asequence having at least about 60%, or at least about 61%, or at leastabout 62%, or at least about 63%, or at least about 64%, or at leastabout 65%, or at least about 66%, or at least about 67%, or at leastabout 68%, or at least about 69%, or at least about 70%, or at leastabout 71%, or at least about 72%, or at least about 73%, or at leastabout 74%, or at least about 75%, or at least about 76%, or at leastabout 77%, or at least about 78%, or at least about 79%, or at leastabout 80%, or at least about 81%, or at least about 82%, or at leastabout 83%, or at least about 84%, or at least about 85%, or at leastabout 86%, or at least about 87%, or at least about 88%, or at leastabout 89%, or at least about 90%, or at least about 91%, or at leastabout 92%, or at least about 93%, or at least about 94%, or at leastabout 95%, or at least about 96%, or at least about 97%, or at leastabout 98%, or at least about 99%) sequence identity with the known aminoacid or nucleic acid sequence of the extracellular domains, e.g. humanextracellular domains, e.g. one or more of SEQ IDs NOs: 1-15 as a wholeor relative to indicated domains therein. Included herein are variousillustrative sequences, as SEQ IDs NOs: 1-15, which show extracellulardomains as underlined or in bold and a linker in normal text. In variousembodiments, the linker can be swapped for another described herein.

In an illustrative embodiment, the chimeric protein of the presentinvention comprises an extracellular domain of PD-1 and theextracellular domain of OX40L using the hinge-CH2-CH3 domain from ahuman IgG4 antibody sequence. In this embodiment, the extracellulardomain of PD-1 is underlined, followed by the hinge-CH2-CH3 domain ofhuman IgG4 and short linker (normal text), followed by the extracellulardomain of OX40L (bold text):

(SEQ ID NO: 1) ATGCAGATCCCACAGGCGCCCTGGCCAGTCGTCTGGGCGGTGCTACAACTGGGCTGGCGGCCAGGATGGTTCTTAGACTCCCCAGACAGGCCCTGGAACCCCCCCACCTTCTCCCCAGCCCTGCTCGTGGTGACCGAAGGGGACAACGCCACCTTCACCTGCAGCTTCTCCAACACATCGGAGAGCTTCGTGCTAAACTGGTACCGCATGAGCCCCAGCAACCAGACGGACAAGCTGGCCGCCTTCCCCGAGGACCGCAGCCAGCCCGGCCAGGACTGCCGCTTCCGTGTCACACAACTGCCCAACGGGCGTGACTTCCACATGAGCGTGGTCAGGGCCCGGCGCAATGACAGCGGCACCTACCTCTGTGGGGCCATCTCCCTGGCCCCCAAGGCGCAGATCAAAGAGAGCCTGCGGGCAGAGCTCAGGGTGACAGAGAGAAGGGCAGAAGTGCCCACAGCCCACCCCAGCCCCTCACCCAGGCCAGCCGGCCAGTTCCAATCTAAGTACGGCCCTCCCTGCCCTAGCTGTCCCGCCCCTGAATTTCTGGGCGGACCCTCCGTGTTTCTGTTCCCCCCAAAGCCCAAGGACACCCTGATGATCAGCCGGACCCCCGAAGTGACCTGTGTGGTGGTGGATGTGTCCCAGGAAGATCCCGAGGTGCAGTTCAATTGGTACGTGGACGGGGTGGAAGTGCACAACGCCAAGACCAAGCCCAGAGAGGAACAGTTCAACAGCACCTACCGGGTGGTGTCTGTGCTGACCGTGCTGCACCAGGATTGGCTGAGCGGCAAAGAGTACAAGTGCAAGGTGTCCAGCAAGGGCCTGCCCAGCAGCATCGAAAAGACCATCAGCAACGCCACCGGCCAGCCCAGGGAACCCCAGGTGTACACACTGCCCCCTAGCCAGGAAGAGATGACCAAGAACCAGGTGTCCCTGACATGCCTCGTGAAGGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGAGCAACGGCCAGCCAGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCTCATTCTTCCTGTACTCCCGGCTGACAGTGGACAAGAGCAGCTGGCAGGAAGGCAACGTGTTCAGCTGCAGCGTGATGCACGAAGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGTCCCTGGGCAAAATAGAGGGACGAATGGACCAGGTATCACATCGGTATCCTCGAATTCAAAGTATCAAAGTACAATTTACCGAATATAAGAAGGAGAAAGGTTTCATCCTCACTTCCCAAAAGGAGGATGAAATCATGAAGGTGCAGAACAACTCAGTCATCATCAACTGTGATGGGTTTTATCTCATCTCCCTGAAGGGCTACTTCTCCCAGGAAGTCAACATTAGCCTTCATTACCAGAAGGATGAGGAGCCCCTCTTCCAACTGAAGAAGGTCAGGTCTGTCAACTCCTTGATGGTGGCCTCTCTGACTTACAAAGACAAAGTCTACTTGAATGTGACCACTGACAATACCTCCCTGGATGACTTCCATGTGAATGGCGGAGAACTGATTCTTATCCATCAAAATCCTGGTGAATTCTGTGTCCTTTGA.

This sequence encodes a protein with an amino acid sequence:

(SEQ ID NO: 2) MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQSKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNATGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSSWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKIEGRMDQVSHRYPRIQSIKVQFTEYKKEKGFILTSQKEDEIMKVQNNSVIINCDGFYLISLKGYFSQEVNISLHYQKDEEPLFQLKKVRSVNSLMVASLTYKDKVYLNVTTDNTSLDDFHVNGGELILIHQNPGEFCVLStop

Further, this amino acid sequence, as well as the amino acid sequencesof any of the extracellular domains described herein (whether or notexplicitly listed) could also be achieved with codon-optimized nucleicacid sequences, such as the following sequence which is optimized forexpression by Chinese Hamster (CHO) cells:

(SEQ ID NO: 3) ATGCAGATTCCTCAGGCCCCTTGGCCTGTCGTGTGGGCTGTGCTGCAGCTGGGATGGCGGCCTGGCTGGTTTCTGGACAGCCCCGACAGACCCTGGAACCCCCCTACATTTTCCCCTGCCCTGCTGGTCGTGACCGAGGGCGACAATGCCACCTTCACCTGTAGCTTCAGCAACACCAGCGAGAGCTTCGTGCTGAACTGGTACAGAATGAGCCCCAGCAACCAGACCGACAAGCTGGCCGCCTTCCCCGAGGATAGATCTCAGCCCGGCCAGGACTGCCGGTTCAGAGTGACCCAGCTGCCCAACGGCCGGGACTTCCACATGTCTGTCGTGCGGGCCAGACGGAACGACAGCGGCACATATCTGTGCGGCGCCATCAGCCTGGCCCCCAAGGCCCAGATCAAAGAGAGCCTGAGAGCCGAGCTGAGAGTGACCGAGAGAAGGGCCGAAGTGCCTACCGCCCACCCTAGCCCATCTCCAAGACCTGCCGGCCAGTTCCAGTCTAAGTACGGCCCTCCTTGCCCCAGCTGTCCCGCCCCTGAATTTCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCAAAGCCCAAGGACACCCTGATGATCAGCCGGACCCCCGAAGTGACCTGCGTGGTGGTGGATGTGTCCCAGGAAGATCCCGAGGTGCAGTTCAATTGGTACGTGGACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCCAGAGAGGAACAGTTCAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAGCGGCAAAGAGTACAAGTGCAAGGTGTCCAGCAAGGGCCTGCCCAGCAGCATCGAGAAAACCATCAGCAACGCCACCGGCCAGCCCAGGGAACCCCAGGTGTACACACTGCCCCCTAGCCAGGAAGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTCGTGAAGGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGAGCAACGGCCAGCCTGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCTCATTTTTCCTGTACTCCAGACTGACCGTGGACAAGAGCAGCTGGCAGGAAGGCAACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGTCTCTGAGCCTGGGCAAGATCGAGGGCCGGATGGATAGAGCCCAGGGCGAAGCCTGCGTGCAGTTCCAGGCTCTGAAGGGCCAGGAATTCGCCCCCAGCCACCAGCAGGTGTACGCCCCTCTGAGAGCTGACGGCGACAAGCCTAGAGCCCACCTGACAGTCGTGCGGCAGACCCCTACCCAGCACTTCAAGAATCAGTTCCCAGCCCTGCACTGGGAGCACGAGCTGGGCCTGGCCTTCACCAAGAACAGAATGAACTACACCAACAAGTTTCTGCTGATCCCCGAGAGCGGCGACTACTTCATCTACAGCCAAGTGACCTTCCGGGGCATGACCAGCGAGTGCAGCGAGATCAGACAGGCCGGCAGACCTAACAAGCCCGACAGCATCACCGTCGTGATCACCAAAGTGACCGACAGCTACCCCGAGCCCACACAGCTGCTGATGGGCACCAAGAGCGTGTGCGAAGTGGGCAGCAACTGGTTCCAGCCCATCTACCTGGGCGCCATGTTCAGTCTGCAAGAGGGCGATAAGCTGATGGTCAACGTGTCCGACATCTCCCTGGTGGATTACACCAAAGAGGACAAGACCTTCTTCGGCGCCTTTCT GCTCTGA

Another embodiment of the present chimeric protein comprises theextracellular domain of PD-1 and the extracellular domain ofcostimulatory ligand, such as TL1A, 4-1BBL, ICOSL, GITRL, CD27 or CD40L.An example sequence encoding the extracellular domain of PD-1(underlined) −Fc (normal text)-the extracellular domain of TL1A (boldtext) is:

(SEQ ID NO: 4) ATGCAGATCCCACAGGCGCCCTGGCCAGTCGTCTGGGCGGTGCTACAACTGGGCTGGCGGCCAGGATGGTTCTTAGACTCCCCAGACAGGCCCTGGAACCCCCCCACCTTCTCCCCAGCCCTGCTCGTGGTGACCGAAGGGGACAACGCCACCTTCACCTGCAGCTTCTCCAACACATCGGAGAGCTTCGTGCTAAACTGGTACCGCATGAGCCCCAGCAACCAGACGGACAAGCTGGCCGCCTTCCCCGAGGACCGCAGCCAGCCCGGCCAGGACTGCCGCTTCCGTGTCACACAACTGCCCAACGGGCGTGACTTCCACATGAGCGTGGTCAGGGCCCGGCGCAATGACAGCGGCACCTACCTCTGTGGGGCCATCTCCCTGGCCCCCAAGGCGCAGATCAAAGAGAGCCTGCGGGCAGAGCTCAGGGTGACAGAGAGAAGGGCAGAAGTGCCCACAGCCCACCCCAGCCCCTCACCCAGGCCAGCCGGCCAGTTCCAATCTAAGTACGGCCCTCCCTGCCCTAGCTGTCCCGCCCCTGAATTTCTGGGCGGACCCTCCGTGTTTCTGTTCCCCCCAAAGCCCAAGGACACCCTGATGATCAGCCGGACCCCCGAAGTGACCTGTGTGGTGGTGGATGTGTCCCAGGAAGATCCCGAGGTGCAGTTCAATTGGTACGTGGACGGGGTGGAAGTGCACAACGCCAAGACCAAGCCCAGAGAGGAACAGTTCAACAGCACCTACCGGGTGGTGTCTGTGCTGACCGTGCTGCACCAGGATTGGCTGAGCGGCAAAGAGTACAAGTGCAAGGTGTCCAGCAAGGGCCTGCCCAGCAGCATCGAAAAGACCATCAGCAACGCCACCGGCCAGCCCAGGGAACCCCAGGTGTACACACTGCCCCCTAGCCAGGAAGAGATGACCAAGAACCAGGTGTCCCTGACATGCCTCGTGAAGGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGAGCAACGGCCAGCCAGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCTCATTCTTCCTGTACTCCCGGCTGACAGTGGACAAGAGCAGCTGGCAGGAAGGCAACGTGTTCAGCTGCAGCGTGATGCACGAAGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGTCCCTGGGCAAAATAGAGGGACGAATGGACCGGGCCCAGGGAGAGGCCTGTGTGCAGTTCCAGGCTCTAAAAGGACAGGAGTTTGCACCTTCACATCAGCAAGTTTATGCACCTCTTAGAGCAGACGGAGATAAGCCAAGGGCACACCTGACAGTTGTGAGACAAACTCCCACACAGCACTTTAAAAATCAGTTCCCAGCTCTGCACTGGGAACATGAACTAGGCCTGGCCTTCACCAAGAACCGAATGAACTATACCAACAAATTCCTGCTGATCCCAGAGTCGGGAGACTACTTCATTTACTCCCAGGTCACATTCCGTGGGATGACCTCTGAGTGCAGTGAAATCAGACAAGCAGGCCGACCAAACAAGCCAGACTCCATCACTGTGGTCATCACCAAGGTAACAGACAGCTACCCTGAGCCAACCCAGCTCCTCATGGGGACCAAGTCTGTATGCGAAGTAGGTAGCAACTGGTTCCAGCCCATCTACCTCGGAGCCATGTTCTCCTTGCAAGAAGGGGACAAGCTAATGGTGAACGTCAGTGACATCTCTTTGGTGGATTACACAAAAGAAGATAAAACCTTCTTTGGAGCCTTCTTACTAT AG

This nucleotide sequence of SEQ ID NO: 4 may be codon optimized, toencode a protein with an amino acid sequence:

(SEQ ID NO: 5) MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQSKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNATGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSSWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKIEGRMDRAQGEACVQFQALKGQEFAPSHQQVYAPLRADGDKPRAHLTVVRQTPTQHFKNQFPALHWEHELGLAFTKNRMNYTNKFLLIPESGDYFIYSQVTFRGMTSECSEIRQAGRPNKPDSITVVITKVTDSYPEPTQLLMGTKSVCEVGSNWFQPIYLGAMFSLQEGDKLMVNVSDISLVDYTKEDKTFFGAFLLStop

There are many type I membrane proteins expressed by tumor cells thatcould be masked by a fusion protein encoding the extracellular domain ofa cognate receptor. Additional examples would include a fusion proteinencoding the extracellular domain of BTLA, linked through an Fc toOX40L. Such a construct could be encoded by the nucleic acid sequence:

(SEQ ID NO: 6) ATGAAGACATTGCCTGCCATGCTTGGAACTGGGAAATTATTTTGGGTCTTCTTCTTAATCCCATATCTGGACATCTGGAACATCCATGGGAAAGAATCATGTGATGTACAGCTTTATATAAAGAGACAATCTGAACACTCCATCTTAGCAGGAGATCCCTTTGAACTAGAATGCCCTGTGAAATACTGTGCTAACAGGCCTCATGTGACTTGGTGCAAGCTCAATGGAACAACATGTGTAAAACTTGAAGATAGACAAACAAGTTGGAAGGAAGAGAAGAACATTTCATTTTTCATTCTACATTTTGAACCAGTGCTTCCTAATGACAATGGGTCATACCGCTGTTCTGCAAATTTTCAGTCTAATCTCATTGAAAGCCACTCAACAACTCTTTATGTGACAGATGTAAAAAGTGCCTCAGAACGACCCTCCAAGGACGAAATGGCAAGCTCTAAGTACGGCCCTCCCTGCCCTAGCTGTCCCGCCCCTGAATTTCTGGGCGGACCCTCCGTGTTTCTGTTCCCCCCAAAGCCCAAGGACACCCTGATGATCAGCCGGACCCCCGAAGTGACCTGTGTGGTGGTGGATGTGTCCCAGGAAGATCCCGAGGTGCAGTTCAATTGGTACGTGGACGGGGTGGAAGTGCACAACGCCAAGACCAAGCCCAGAGAGGAACAGTTCAACAGCACCTACCGGGTGGTGTCTGTGCTGACCGTGCTGCACCAGGATTGGCTGAGCGGCAAAGAGTACAAGTGCAAGGTGTCCAGCAAGGGCCTGCCCAGCAGCATCGAAAAGACCATCAGCAACGCCACCGGCCAGCCCAGGGAACCCCAGGTGTACACACTGCCCCCTAGCCAGGAAGAGATGACCAAGAACCAGGTGTCCCTGACATGCCTCGTGAAGGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGAGCAACGGCCAGCCAGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCTCATTCTTCCTGTACTCCCGGCTGACAGTGGACAAGAGCAGCTGGCAGGAAGGCAACGTGTTCAGCTGCAGCGTGATGCACGAAGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGTCCCTGGGCAAAATAGAGGGACGAATGGACCAGGTATCACATCGGTATCCTCGAATTCAAAGTATCAAAGTACAATTTACCGAATATAAGAAGGAGAAAGGTTTCATCCTCACTTCCCAAAAGGAGGATGAAATCATGAAGGTGCAGAACAACTCAGTCATCATCAACTGTGATGGGTTTTATCTCATCTCCCTGAAGGGCTACTTCTCCCAGGAAGTCAACATTAGCCTTCATTACCAGAAGGATGAGGAGCCCCTCTTCCAACTGAAGAAGGTCAGGTCTGTCAACTCCTTGATGGTGGCCTCTCTGACTTACAAAGACAAAGTCTACTTGAATGTGACCACTGACAATACCTCCCTGGATGACTTCCATGTGAATGGCGGAGAACTGATTCTTATCCATCAAAATCCTGG TGAATTCTGTGTCCTTTGA

This nucleotide sequence encodes a protein with an amino acid sequence:

(SEQ ID NO: 7) MKTLPAMLGTGKLFWVFFLIPYLDIWNIHGKESCDVQLYIKRQSEHSILAGDPFELECPVKYCANRPHVTWCKLNGTTCVKLEDRQTSWKEEKNISFFILHFEPVLPNDNGSYRCSANFQSNLIESHSTTLYVTDVKSASERPSKDEMASSKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNATGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSSWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKIEGRMDQVSHRYPRIQSIKVQFTEYKKEKGFILTSQKEDEIMKVQNNSVIINCDGFYLISLKGYFSQEVNISLHYQKDEEPLFQLKKVRSVNSLMVASLTYKDKVYLNVTTDNTSLDDFHVNGGELILIHQN PGEFCVLStop

Another example would include a fusion protein incorporating theextracellular domain of TIGIT, linked via an Fc linker to OX40L:

(SEQ ID NO: 8) ATGCGCTGGTGTCTCCTCCTGATCTGGGCCCAGGGGCTGAGGCAGGCTCCCCTCGCCTCAGGAATGATGACAGGCACAATAGAAACAACGGGGAACATTTCTGCAGAGAAAGGTGGCTCTATCATCTTACAATGTCACCTCTCCTCCACCACGGCACAAGTGACCCAGGTCAACTGGGAGCAGCAGGACCAGCTTCTGGCCATTTGTAATGCTGACTTGGGGTGGCACATCTCCCCATCCTTCAAGGATCGAGTGGCCCCAGGTCCCGGCCTGGGCCTCACCCTCCAGTCGCTGACCGTGAACGATACAGGGGAGTACTTCTGCATCTATCACACCTACCCTGATGGGACGTACACTGGGAGAATCTTCCTGGAGGTCCTAGAAAGCTCAGTGGCTGAGCACGGTGCCAGGTTCCAGATTCCATCTAAGTACGGCCCTCCCTGCCCTAGCTGTCCCGCCCCTGAATTTCTGGGCGGACCCTCCGTGTTTCTGTTCCCCCCAAAGCCCAAGGACACCCTGATGATCAGCCGGACCCCCGAAGTGACCTGTGTGGTGGTGGATGTGTCCCAGGAAGATCCCGAGGTGCAGTTCAATTGGTACGTGGACGGGGTGGAAGTGCACAACGCCAAGACCAAGCCCAGAGAGGAACAGTTCAACAGCACCTACCGGGTGGTGTCTGTGCTGACCGTGCTGCACCAGGATTGGCTGAGCGGCAAAGAGTACAAGTGCAAGGTGTCCAGCAAGGGCCTGCCCAGCAGCATCGAAAAGACCATCAGCAACGCCACCGGCCAGCCCAGGGAACCCCAGGTGTACACACTGCCCCCTAGCCAGGAAGAGATGACCAAGAACCAGGTGTCCCTGACATGCCTCGTGAAGGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGAGCAACGGCCAGCCAGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCTCATTCTTCCTGTACTCCCGGCTGACAGTGGACAAGAGCAGCTGGCAGGAAGGCAACGTGTTCAGCTGCAGCGTGATGCACGAAGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGTCCCTGGGCAAAATAGAGGGACGAATGGACCAGGTATCACATCGGTATCCTCGAATTCAAAGTATCAAAGTACAATTTACCGAATATAAGAAGGAGAAAGGTTTCATCCTCACTTCCCAAAAGGAGGATGAAATCATGAAGGTGCAGAACAACTCAGTCATCATCAACTGTGATGGGTTTTATCTCATCTCCCTGAAGGGCTACTTCTCCCAGGAAGTCAACATTAGCCTTCATTACCAGAAGGATGAGGAGCCCCTCTTCCAACTGAAGAAGGTCAGGTCTGTCAACTCCTTGATGGTGGCCTCTCTGACTTACAAAGACAAAGTCTACTTGAATGTGACCACTGACAATACCTCCCTGGATGACTTCCATGTGAATGGCGGAGAACTGATTCTTATCCATCAAAATCCTGGTGAATTCTGTGTCCTT TGA.

This sequence could be codon optimized to encode a protein with an aminoacid sequence:

(SEQ ID NO: 9) MRWCLLLIWAQGLRQAPLASGMMTGTIETTGNISAEKGGSIILQCHLSSTTAQVTQVNWEQQDQLLAI CNADLGWHISPSFKDRVAPGPGLGLTLQSLTVNDTGEYFCIYHTYPDGTYTGRIFLEVLESSVAEHG ARFQIPSKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVD GVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNATGQPREPQ VYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SSWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKIEGRMDQVSHRYPRIQSIKVQFTEYKKEKGFILT SQKEDEIMKVQNNSVIINCDGFYLISLKGYFSQEVNISLHYQKDEEPLFQLKKVRSVNSLMVASLTY KDKVYLNVTTDNTSLDDFHVNGGELILIHQNPGEFCVL Stop.

Another example would include a fusion protein incorporating theextracellular domain of TIM3, linked through an Fc region to humanOX40L:

(SEQ ID NO: 10) ATGTTTTCACATCTTCCCTTTGACTGTGTCCTGCTGCTGCTGCTGCTACTACTTACAAGGTCCTCAGAAGTGGAATACAGAGCGGAGGTCGGTCAGAATGCCTATCTGCCCTGCTTCTACACCCCAGCCGCCCCAGGGAACCTCGTGCCCGTCTGCTGGGGCAAAGGAGCCTGTCCTGTGTTTGAATGTGGCAACGTGGTGCTCAGGACTGATGAAAGGGATGTGAATTATTGGACATCCAGATACTGGCTAAATGGGGATTTCCGCAAAGGAGATGTGTCCCTGACCATAGAGAATGTGACTCTAGCAGACAGTGGGATCTACTGCTGCCGGATCCAAATCCCAGGCATAATGAATGATGAAAAATTTAACCTGAAGTTGGTCATCAAACCAGCCAAGGTCACCCCTGCACCGACTCGGCAGAGAGACTTCACTGCAGCCTTTCCAAGGATGCTTACCACCAGGGGACATGGCCCAGCAGAGACACAGACACTGGGGAGCCTCCCTGATATAAATCTAACACAAATATCCACATTGGCCAATGAGTTACGGGACTCTAGATTGGCCAATGACTTACGGGACTCTGGAGCAACCATCAGAATAGGCTCTAAGTACGGCCCTCCCTGCCCTAGCTGTCCCGCCCCTGAATTTCTGGGCGGACCCTCCGTGTTTCTGTTCCCCCCAAAGCCCAAGGACACCCTGATGATCAGCCGGACCCCCGAAGTGACCTGTGTGGTGGTGGATGTGTCCCAGGAAGATCCCGAGGTGCAGTTCAATTGGTACGTGGACGGGGTGGAAGTGCACAACGCCAAGACCAAGCCCAGAGAGGAACAGTTCAACAGCACCTACCGGGTGGTGTCTGTGCTGACCGTGCTGCACCAGGATTGGCTGAGCGGCAAAGAGTACAAGTGCAAGGTGTCCAGCAAGGGCCTGCCCAGCAGCATCGAAAAGACCATCAGCAACGCCACCGGCCAGCCCAGGGAACCCCAGGTGTACACACTGCCCCCTAGCCAGGAAGAGATGACCAAGAACCAGGTGTCCCTGACATGCCTCGTGAAGGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGAGCAACGGCCAGCCAGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCTCATTCTTCCTGTACTCCCGGCTGACAGTGGACAAGAGCAGCTGGCAGGAAGGCAACGTGTTCAGCTGCAGCGTGATGCACGAAGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGTCCCTGGGCAAAATAGAGGGACGAATGGACCAGGTATCACATCGGTATCCTCGAATTCAAAGTATCAAAGTACAATTTACCGAATATAAGAAGGAGAAAGGTTTCATCCTCACTTCCCAAAAGGAGGATGAAATCATGAAGGTGCAGAACAACTCAGTCATCATCAACTGTGATGGGTTTTATCTCATCTCCCTGAAGGGCTACTTCTCCCAGGAAGTCAACATTAGCCTTCATTACCAGAAGGATGAGGAGCCCCTCTTCCAACTGAAGAAGGTCAGGTCTGTCAACTCCTTGATGGTGGCCTCTCTGACTTACAAAGACAAAGTCTACTTGAATGTGACCACTGACAATACCTCCCTGGATGACTTCCATGTGAATGGCGGAGAACTGATTCTTATCCATCAAAATCCTGGTGAATTCTGTGTC CTTTGA.

Such a sequence could be codon optimized to encode a protein with anamino acid sequence:

(SEQ ID NO: 11) MFSHLPFDCVLLLLLLLLTRSSEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPVFECGNVV LRTDERDVNYWTSRYWLNGDFRKGDVSLTIENVTLADSGIYCCRIQIPGIMNDEKFNLKLVIKPAKVT PAPTRQRDFTAAFPRMLTTRGHGPAETQTLGSLPDINLTQISTLANELRDSRLANDLRDSGATIRIGS KYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNA KTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNATGQPREPQVYTLPPS QEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSSWQEG NVFSCSVMHEALHNHYTQKSLSLSLGKIEGRMDQVSHRYPRIQSIKVQFTEYKKEKGFILTSQKEDE IMKVQNNSVIINCDGFYLISLKGYFSQEVNISLHYQKDEEPLFQLKKVRSVNSLMVASLTYKDKVYLN VTTDNTSLDDFHVNGGELILIHQNPGEFCVL Stop.

Another example could include the extracellular domain of CD172aadjoined with an Fc linker sequence to the extracellular domain of humanOX40L:

(SEQ ID NO: 12) ATGGAGCCCGCCGGCCCGGCCCCCGGCCGCCTCGGGCCGCTGCTCTGCCTGCTGCTCGCCGCGTCCTGCGCCTGGTCAGGAGTGGCGGGTGAGGAGGAGCTGCAGGTGATTCAGCCTGACAAGTCCGTGTTGGTTGCAGCTGGAGAGACAGCCACTCTGCGCTGCACTGCGACCTCTCTGATCCCTGTGGGGCCCATCCAGTGGTTCAGAGGAGCTGGACCAGGCCGGGAATTAATCTACAATCAAAAAGAAGGCCACTTCCCCCGGGTAACAACTGTTTCAGACCTCACAAAGAGAAACAACATGGACTTTTCCATCCGCATCGGTAACATCACCCCAGCAGATGCCGGCACCTACTACTGTGTGAAGTTCCGGAAAGGGAGCCCCGATGACGTGGAGTTTAAGTCTGGAGCAGGCACTGAGCTGTCTGTGCGCGCCAAACCCTCTGCCCCCGTGGTATCGGGCCCTGCGGCGAGGGCCACACCTCAGCACACAGTGAGCTTCACCTGCGAGTCCCACGGCTTCTCACCCAGAGACATCACCCTGAAATGGTTCAAAAATGGGAATGAGCTCTCAGACTTCCAGACCAACGTGGACCCCGTAGGAGAGAGCGTGTCCTACAGCATCCACAGCACAGCCAAGGTGGTGCTGACCCGCGAGGACGTTCACTCTCAAGTCATCTGCGAGGTGGCCCACGTCACCTTGCAGGGGGACCCTCTTCGTGGGACTGCCAACTTGTCTGAGACCATCCGAGTTCCACCCACCTTGGAGGTTACTCAACAGCCCGTGAGGGCAGAGAACCAGGTGAATGTCACCTGCCAGGTGAGGAAGTTCTACCCCCAGAGACTACAGCTGACCTGGTTGGAGAATGGAAACGTGTCCCGGACAGAAACGGCCTCAACCGTTACAGAGAACAAGGATGGTACCTACAACTGGATGAGCTGGCTCCTGGTGAATGTATCTGCCCACAGGGATGATGTGAAGCTCACCTGCCAGGTGGAGCATGACGGGCAGCCAGCGGTCAGCAAAAGCCATGACCTGAAGGTCTCAGCCCACCCGAAGGAGCAGGGCTCAAATACCGCCGCTGAGAACACTGGATCTAATGAACGGAACATCTATTCTAAGTACGGCCCTCCCTGCCCTAGCTGTCCCGCCCCTGAATTTCTGGGCGGACCCTCCGTGTTTCTGTTCCCCCCAAAGCCCAAGGACACCCTGATGATCAGCCGGACCCCCGAAGTGACCTGTGTGGTGGTGGATGTGTCCCAGGAAGATCCCGAGGTGCAGTTCAATTGGTACGTGGACGGGGTGGAAGTGCACAACGCCAAGACCAAGCCCAGAGAGGAACAGTTCAACAGCACCTACCGGGTGGTGTCTGTGCTGACCGTGCTGCACCAGGATTGGCTGAGCGGCAAAGAGTACAAGTGCAAGGTGTCCAGCAAGGGCCTGCCCAGCAGCATCGAAAAGACCATCAGCAACGCCACCGGCCAGCCCAGGGAACCCCAGGTGTACACACTGCCCCCTAGCCAGGAAGAGATGACCAAGAACCAGGTGTCCCTGACATGCCTCGTGAAGGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGAGCAACGGCCAGCCAGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCTCATTCTTCCTGTACTCCCGGCTGACAGTGGACAAGAGCAGCTGGCAGGAAGGCAACGTGTTCAGCTGCAGCGTGATGCACGAAGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGTCCCTGGGCAAAATAGAGGGACGAATGGACCAGGTATCACATCGGTATCCTCGAATTCAAAGTATCAAAGTACAATTTACCGAATATAAGAAGGAGAAAGGTTTCATCCTCACTTCCCAAAAGGAGGATGAAATCATGAAGGTGCAGAACAACTCAGTCATCATCAACTGTGATGGGTTTTATCTCATCTCCCTGAAGGGCTACTTCTCCCAGGAAGTCAACATTAGCCTTCATTACCAGAAGGATGAGGAGCCCCTCTTCCAACTGAAGAAGGTCAGGTCTGTCAACTCCTTGATGGTGGCCTCTCTGACTTACAAAGACAAAGTCTACTTGAATGTGACCACTGACAATACCTCCCTGGATGACTTCCATGTGAATGGCGGAGAACTGATTCTTATCCATCAAAATCCTGGTGAATTCTGTGTCCTTTGA.

Such a sequence could be codon optimized to encode a protein with anamino acid sequence:

(SEQ ID NO: 13) MEPAGPAPGRLGPLLCLLLAASCAWSGVAGEEELQVIQPDKSVLVAAGETATLRCTATSLIPVGPIQ WFRGAGPGRELIYNQKEGHFPRVTTVSDLTKRNNMDFSIRIGNITPADAGTYYCVKFRKGSPDDVEF KSGAGTELSVRAKPSAPVVSGPAARATPQHTVSFTCESHGFSPRDITLKWFKNGNELSDFQTNVDP VGESVSYSIHSTAKVVLTREDVHSQVICEVAHVTLQGDPLRGTANLSETIRVPPTLEVTQQPVRAENQ VNVTCQVRKFYPQRLQLTWLENGNVSRTETASTVTENKDGTYNWMSWLLVNVSAHRDDVKLTCQVE HDGQPAVSKSHDLKVSAHPKEQGSNTAAENTGSNERNIYSKYGPPCPSCPAPEFLGGPSVFLFPPKP KDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDW LSGKEYKCKVSSKGLPSSIEKTISNATGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSSWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK IEGRMDQVSHRYPRIQSIKVQFTEYKKEKGFILTSQKEDEIMKVQNNSVIINCDGFYLISLKGYFSQE VNISLHYQKDEEPLFQLKKVRSVNSLMVASLTYKDKVYLNVTTDNTSLDDFHVNGGELILIHQNPGE FCVL Stop.

Another example could include the extracellular domain of TMIGD2adjoined with an Fc linker sequence to the extracellular domain of humanOX40L:

(SEQ ID NO: 14) ATGGGGTCCCCGGGCATGGTGCTGGGCCTCCTGGTGCAGATCTGGGCCCTGCAAGAAGCCTCAAGCCTGAGCGTGCAGCAGGGGCCCAACTTGCTGCAGGTGAGGCAGGGCAGTCAGGCGACCCTGGTCTGCCAGGTGGACCAGGCCACAGCCTGGGAACGGCTCCGTGTTAAGTGGACAAAGGATGGGGCCATCCTGTGTCAACCGTACATCACCAACGGCAGCCTCAGCCTGGGGGTCTGCGGGCCCCAGGGACGGCTCTCCTGGCAGGCACCCAGCCATCTCACCCTGCAGCTGGACCCTGTGAGCCTCAACCACAGCGGGGCGTACGTGTGCTGGGCGGCCGTAGAGATTCCTGAGTTGGAGGAGGCTGAGGGCAACATAACAAGGCTCTTTGTGGACCCAGATGACCCCACACAGAACAGAAACCGGATCGCAAGCTTCCCAGGATCTAAGTACGGCCCTCCCTGCCCTAGCTGTCCCGCCCCTGAATTTCTGGGCGGACCCTCCGTGTTTCTGTTCCCCCCAAAGCCCAAGGACACCCTGATGATCAGCCGGACCCCCGAAGTGACCTGTGTGGTGGTGGATGTGTCCCAGGAAGATCCCGAGGTGCAGTTCAATTGGTACGTGGACGGGGTGGAAGTGCACAACGCCAAGACCAAGCCCAGAGAGGAACAGTTCAACAGCACCTACCGGGTGGTGTCTGTGCTGACCGTGCTGCACCAGGATTGGCTGAGCGGCAAAGAGTACAAGTGCAAGGTGTCCAGCAAGGGCCTGCCCAGCAGCATCGAAAAGACCATCAGCAACGCCACCGGCCAGCCCAGGGAACCCCAGGTGTACACACTGCCCCCTAGCCAGGAAGAGATGACCAAGAACCAGGTGTCCCTGACATGCCTCGTGAAGGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGAGCAACGGCCAGCCAGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCTCATTCTTCCTGTACTCCCGGCTGACAGTGGACAAGAGCAGCTGGCAGGAAGGCAACGTGTTCAGCTGCAGCGTGATGCACGAAGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGTCCCTGGGCAAAATAGAGGGACGAATGGACCAGGTATCACATCGGTATCCTCGAATTCAAAGTATCAAAGTACAATTTACCGAATATAAGAAGGAGAAAGGTTTCATCCTCACTTCCCAAAAGGAGGATGAAATCATGAAGGTGCAGAACAACTCAGTCATCATCAACTGTGATGGGTTTTATCTCATCTCCCTGAAGGGCTACTTCTCCCAGGAAGTCAACATTAGCCTTCATTACCAGAAGGATGAGGAGCCCCTCTTCCAACTGAAGAAGGTCAGGTCTGTCAACTCCTTGATGGTGGCCTCTCTGACTTACAAAGACAAAGTCTACTTGAATGTGACCACTGACAATACCTCCCTGGATGACTTCCATGTGAATGGCGGAGAACTGATTCTTATCCATCAAAATCCTGGTGAATTCTGTGTCCTTTGA.

Such a sequence could be codon optimized to encode a protein with anamino acid sequence:

(SEQ ID NO: 15) MGSPGMVLGLLVQIWALQEASSLSVQQGPNLLQVRQGSQATLVCQVDQATAWERLRVKWTKDGAIL CQPYITNGSLSLGVCGPQGRLSWQAPSHLTLQLDPVSLNHSGAYVCWAAVEIPELEEAEGNITRLFV DPDDPTQNRNRIASFPGSKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQE DPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTI SNATGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSRLTVDKSSWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKIEGRMDQVSHRYPRIQSIKVQF TEYKKEKGFILTSQKEDEIMKVQNNSVIINCDGFYLISLKGYFSQEVNISLHYQKDEEPLFQLKKVRS VNSLMVASLTYKDKVYLNVTTDNTSLDDFHVNGGELILIHQNPGEFCVL Stop

In various embodiments, the chimeric protein may comprise an amino acidsequence having one or more amino acid mutations relative to any of theprotein sequences described herein. In some embodiments, the one or moreamino acid mutations may be independently selected from substitutions,insertions, deletions, and truncations.

In some embodiments, the amino acid mutations are amino acidsubstitutions, and may include conservative and/or non-conservativesubstitutions.

“Conservative substitutions” may be made, for instance, on the basis ofsimilarity in polarity, charge, size, solubility, hydrophobicity,hydrophilicity, and/or the amphipathic nature of the amino acid residuesinvolved. The 20 naturally occurring amino acids can be grouped into thefollowing six standard amino acid groups: (1) hydrophobic: Met, Ala,Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser, Thr; Asn, Gin; (3)acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that influencechain orientation: Gly, Pro; and (6) aromatic: Trp, Tyr, Phe.

As used herein, “conservative substitutions” are defined as exchanges ofan amino acid by another amino acid listed within the same group of thesix standard amino acid groups shown above. For example, the exchange ofAsp by Glu retains one negative charge in the so modified polypeptide.In addition, glycine and proline may be substituted for one anotherbased on their ability to disrupt α-helices.

As used herein, “non-conservative substitutions” are defined asexchanges of an amino acid by another amino acid listed in a differentgroup of the six standard amino acid groups (1) to (6) shown above.

In various embodiments, the substitutions may also include non-classicalamino acids (e.g. selenocysteine, pyrrolysine, N-formylmethionineβ-alanine, GABA and 6-Aminolevulinic acid, 4-aminobenzoic acid (PABA),D-isomers of the common amino acids, 2,4-diaminobutyric acid, α-aminoisobutyric acid, 4-aminobutyric acid, Abu, 2-amino butyric acid, γ-Abu,ε-Ahx, 6-amino hexanoic acid, Aib, 2-amino isobutyric acid, 3-aminopropionic acid, ornithine, norleucine, norvaline, hydroxyproline,sarcosme, citrulline, homocitrulline, cysteic acid, t-butylglycine,t-butylalanine, phenylglycine, cyclohexylalanine, β-alanine,fluoro-amino acids, designer amino acids such as β methyl amino acids, Cα-methyl amino acids, N α-methyl amino acids, and amino acid analogs ingeneral).

Mutations may also be made to the nucleotide sequences of the chimericproteins by reference to the genetic code, including taking into accountcodon degeneracy.

In various embodiments, the chimeric protein comprises a linker. Invarious embodiments, the linker may be derived from naturally-occurringmulti-domain proteins or are empirical linkers as described, forexample, in Chichili et al., (2013), Protein Sci. 22(2):153-167, Chen etal., (2013), Adv Drug Deliv Rev. 65(10):1357-1369, the entire contentsof which are hereby incorporated by reference. In some embodiments, thelinker may be designed using linker designing databases and computerprograms such as those described in Chen et al., (2013), Adv Drug DelivRev. 65(10):1357-1369 and Crasto et. al., (2000), Protein Eng.13(5):309-312, the entire contents of which are hereby incorporated byreference.

In some embodiments, the linker is a synthetic linker such as PEG.

In other embodiments, the linker is a polypeptide. In some embodiments,the linker is less than about 500 amino acids long, about 450 aminoacids long, about 400 amino acids long, about 350 amino acids long,about 300 amino acids long, about 250 amino acids long, about 200 aminoacids long, about 150 amino acids long, or about 100 amino acids long.For example, the linker may be less than about 100, about 95, about 90,about 85, about 80, about 75, about 70, about 65, about 60, about 55,about 50, about 45, about 40, about 35, about 30, about 25, about 20,about 19, about 18, about 17, about 16, about 15, about 14, about 13,about 12, about 11, about 10, about 9, about 8, about 7, about 6, about5, about 4, about 3, or about 2 amino acids long. In some embodiments,the linker is flexible. In another embodiment, the linker is rigid.

In various embodiments, the linker is substantially comprised of glycineand serine residues (e.g. about 30%, or about 40%, or about 50%, orabout 60%, or about 70%, or about 80%, or about 90%, or about 95%, orabout 97% glycines and serines).

In various embodiments, the linker is a hinge region of an antibody(e.g., of IgG, IgA, IgD, and IgE, inclusive of subclasses (e.g. IgG1,IgG2, IgG3, and IgG4, and IgA1 and IgA2)). The hinge region, found inIgG, IgA, IgD, and IgE class antibodies, acts as a flexible spacer,allowing the Fab portion to move freely in space. In contrast to theconstant regions, the hinge domains are structurally diverse, varying inboth sequence and length among immunoglobulin classes and subclasses.For example, the length and flexibility of the hinge region varies amongthe IgG subclasses. The hinge region of IgG1 encompasses amino acids216-231 and, because it is freely flexible, the Fab fragments can rotateabout their axes of symmetry and move within a sphere centered at thefirst of two inter-heavy chain disulfide bridges. IgG2 has a shorterhinge than IgG1, with 12 amino acid residues and four disulfide bridges.The hinge region of IgG2 lacks a glycine residue, is relatively short,and contains a rigid poly-proline double helix, stabilized by extrainter-heavy chain disulfide bridges. These properties restrict theflexibility of the IgG2 molecule. IgG3 differs from the other subclassesby its unique extended hinge region (about four times as long as theIgG1 hinge), containing 62 amino acids (including 21 prolines and 11cysteines), forming an inflexible poly-proline double helix. In IgG3,the Fab fragments are relatively far away from the Fc fragment, givingthe molecule a greater flexibility. The elongated hinge in IgG3 is alsoresponsible for its higher molecular weight compared to the othersubclasses. The hinge region of IgG4 is shorter than that of IgG1 andits flexibility is intermediate between that of IgG1 and IgG2. Theflexibility of the hinge regions reportedly decreases in the orderIgG3>IgG1>IgG4>IgG2. In other embodiments, the linker may be derivedfrom human IgG4 and contain one or more mutations to enhancedimerization (including S228P) or FcRn binding.

According to crystallographic studies, the immunoglobulin hinge regioncan be further subdivided functionally into three regions: the upperhinge region, the core region, and the lower hinge region. See Shin etal., 1992 Immunological Reviews 130:87. The upper hinge region includesamino acids from the carboxyl end of C_(H1) to the first residue in thehinge that restricts motion, generally the first cysteine residue thatforms an interchain disulfide bond between the two heavy chains. Thelength of the upper hinge region correlates with the segmentalflexibility of the antibody. The core hinge region contains theinter-heavy chain disulfide bridges, and the lower hinge region joinsthe amino terminal end of the C_(H2) domain and includes residues inC_(H2). Id. The core hinge region of wild-type human IgG1 contains thesequence Cys-Pro-Pro-Cys which, when dimerized by disulfide bondformation, results in a cyclic octapeptide believed to act as a pivot,thus conferring flexibility. In various embodiments, the present linkercomprises, one, or two, or three of the upper hinge region, the coreregion, and the lower hinge region of any antibody (e.g., of IgG, IgA,IgD, and IgE, inclusive of subclasses (e.g. IgG1, IgG2, IgG3, and IgG4,and IgA1 and IgA2)). The hinge region may also contain one or moreglycosylation sites, which include a number of structurally distincttypes of sites for carbohydrate attachment. For example, IgA1 containsfive glycosylation sites within a 17-amino-acid segment of the hingeregion, conferring resistance of the hinge region polypeptide tointestinal proteases, considered an advantageous property for asecretory immunoglobulin. In various embodiments, the linker of thepresent invention comprises one or more glycosylation sites.

In various embodiments, the linker comprises an Fc domain of an antibody(e.g., of IgG, IgA, IgD, and IgE, inclusive of subclasses (e.g. IgG1,IgG2, IgG3, and IgG4, and IgA1 and IgA2)). In various embodiments, thelinker comprises a hinge-CH2-CH3 Fc domain derived from a human IgG4antibody. In various embodiments, the linker comprises a hinge-CH2-CH3Fc domain derived from a human IgG1 antibody. In some embodiments, theFc domain exhibits increased affinity for and enhanced binding to theneonatal Fc receptor (FcRn). In some embodiments, the Fc domain includesone or more mutations that increases the affinity and enhances bindingto FcRn. Without wishing to be bound by theory, it is believed thatincreased affinity and enhanced binding to FcRn increases the in vivohalf-life of the present chimeric proteins.

In some embodiments, the Fc domain linker contains one or more aminoacid substitutions at amino acid residue 250, 252, 254, 256, 308, 309,311, 428, 433 or 434 (in accordance with Kabat numbering), orequivalents thereof. In an embodiment, the amino acid substitution atamino acid residue 250 is a substitution with glutamine. In anembodiment, the amino acid substitution at amino acid residue 252 is asubstitution with tyrosine, phenylalanine, tryptophan or threonine. Inan embodiment, the amino acid substitution at amino acid residue 254 isa substitution with threonine. In an embodiment, the amino acidsubstitution at amino acid residue 256 is a substitution with serine,arginine, glutamine, glutamic acid, aspartic acid, or threonine. In anembodiment, the amino acid substitution at amino acid residue 308 is asubstitution with threonine. In an embodiment, the amino acidsubstitution at amino acid residue 309 is a substitution with proline.In an embodiment, the amino acid substitution at amino acid residue 311is a substitution with serine. In an embodiment, the amino acidsubstitution at amino acid residue 385 is a substitution with arginine,aspartic acid, serine, threonine, histidine, lysine, alanine or glycine.In an embodiment, the amino acid substitution at amino acid residue 386is a substitution with threonine, proline, aspartic acid, serine,lysine, arginine, isoleucine, or methionine. In an embodiment, the aminoacid substitution at amino acid residue 387 is a substitution witharginine, proline, histidine, serine, threonine, or alanine. In anembodiment, the amino acid substitution at amino acid residue 389 is asubstitution with proline, serine or asparagine. In an embodiment, theamino acid substitution at amino acid residue 428 is a substitution withleucine. In an embodiment, the amino acid substitution at amino acidresidue 433 is a substitution with arginine, serine, isoleucine,proline, or glutamine. In an embodiment, the amino acid substitution atamino acid residue 434 is a substitution with histidine, phenylalanine,or tyrosine.

In some embodiments, the Fc domain linker (e.g., comprising an IgGconstant region) comprises one or more mutations such as substitutionsat amino acid residue 252, 254, 256, 433, 434, or 436 (in accordancewith Kabat numbering). In an embodiment, the IgG constant regionincludes a triple M252Y/S254T/T256E mutation or YTE mutation. In anotherembodiment, the IgG constant region includes a triple H433K/N434F/Y436Hmutation or KFH mutation. In a further embodiment, the IgG constantregion includes an YTE and KFH mutation in combination.

In some embodiments, the modified humanized antibodies of the inventioncomprise an IgG constant region that contains one or more mutations atamino acid residues 250, 253, 307, 310, 380, 428, 433, 434, and 435.Illustrative mutations include T250Q, M428L, T307A, E380A, 1253A, H310A,M428L, H433K, N434A, N434F, N434S, and H435A. In an embodiment, the IgGconstant region comprises a M428L/N434S mutation or LS mutation. Inanother embodiment, the IgG constant region comprises a T250Q/M428Lmutation or QL mutation. In another embodiment, the IgG constant regioncomprises an N434A mutation. In another embodiment, the IgG constantregion comprises a T307A/E380A/N434A mutation or AAA mutation. Inanother embodiment, the IgG constant region comprises an1253A/H310A/H435A mutation or IHH mutation. In another embodiment, theIgG constant region comprises a H433K/N434F mutation. In anotherembodiment, the IgG constant region comprises a M252Y/S254T/T256E and aH433K/N434F mutation in combination.

Additional exemplary mutations in the IgG constant region are described,for example, in Robbie, et al., Antimicrobial Agents and Chemotherapy(2013), 57(12):6147-6153, Dall'Acqua et al., JBC (2006),281(33):23514-24, Dall'Acqua et al., Journal of Immunology (2002),169:5171-80, Ko et al. Nature (2014) 514:642-645, Grevys et al. Journalof Immunology. (2015), 194(11):5497-508, and U.S. Pat. No. 7,083,784,the entire contents of which are hereby incorporated by reference.

In some embodiments, the linker has the amino acid sequence of SEQ IDNO: 70, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto. In various embodiments, mutations are made to SEQ ID No: 70 toincrease stability and/or half-life. For instance, in some embodiments,the linker has the amino acid sequence of SEQ ID NO: 71 or 72, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto. Anillustrative Fc stabilizing mutant is S228P. Illustrative Fc half-lifeextending mutants are T250Q, M428L, V308T, L309P, and Q311S and thepresent linkers may comprise 1, or 2, or 3, or 4, or 5 of these mutants.

Further, one or more joining linkers may be employed to connect thepresent IgG linkers (e.g. one or SEQ ID NOs: 70, 71, or 71, or at least90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto) and theextracellular domains. For example, any one of SEQ ID NO: 73, SEQ ID NO:74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof may connect an extracellular domain as described hereinand a linker as described herein. Optionally, any one of SEQ ID NO: 73,SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO:78, or variants thereof are displaced between an extracellular domain asdescribed herein and a linker as described herein.

Additional illustrative linkers include, but are not limited to, linkershaving the sequence LE, GGGGS (SEQ ID NO: 23), (GGGGS)_(n) (n=1-4),(Gly)₈, (Gly)₆, (EAAAK)_(n) (n=1-3) (SEQ ID NO: 24), A(EAAAK)_(n)A(n=2-5) (SEQ ID NO: 25), AEAAAKEAAAKA (SEQ ID NO: 26),A(EAAAK)₄ALEA(EAAAK)₄A (SEQ ID NO: 27), PAPAP (SEQ ID NO: 28),KESGSVSSEQLAQFRSLD (SEQ ID NO: 29), EGKSSGSGSESKST (SEQ ID NO: 30),GSAGSAAGSGEF (SEQ ID NO:31), and (XP)_(n), with X designating any aminoacid, e.g., Ala, Lys, or Glu.

In various embodiments, the linker may be functional. For example,without limitation, the linker may function to improve the foldingand/or stability, improve the expression, improve the pharmacokinetics,and/or improve the bioactivity of the present chimeric protein. Inanother example, the linker may function to target the chimeric proteinto a particular cell type or location.

In various embodiments, the present chimeric proteins are capable of,and can be used in methods comprising, promoting immune activation (e.g.against tumors). In various embodiments, the present chimeric proteinsare capable of, and can be used in methods comprising, suppressingimmune inhibition (e.g. that allows tumors to survive). In variousembodiments, the present chimeric proteins provide improved immuneactivation and/or improved suppression of immune inhibition due to theproximity of signaling that is provided by the chimeric nature of theconstructs.

In various embodiments, the present chimeric proteins are capable of, orcan be used in methods comprising, modulating the amplitude of an immuneresponse, e.g. modulating the level of effector output. In someembodiments, e.g. when used for the treatment of cancer, the presentchimeric proteins alter the extent of immune stimulation as compared toimmune inhibition to increase the amplitude of a T cell response,including, without limitation, stimulating increased levels of cytokineproduction, proliferation or target killing potential.

In various embodiments the present chimeric proteins, in someembodiments are capable of, or find use in methods involving, masking aninhibitory ligand on the surface of a tumor cell and replacing thatimmune inhibitory ligand with an immune stimulatory ligand (see, e.g.FIG. 4). For example, a chimeric protein construct comprising (i) theextracellular domain of PD-1 and (ii) extracellular domain of OX40L,allows for the disruption of an inhibitory PD-L1 signal and replacing itwith a stimulating OX40L. Accordingly, the present chimeric proteins, insome embodiments are capable of, or find use in methods involving,reducing or eliminating an inhibitory immune signal and/or increasing oractivating an immune stimulatory signal. For example, a tumor cellbearing an inhibitory signal (and thus evading an immune response) maybe substituted for a positive signal binding on a T cell that can thenattack a tumor cell. Accordingly, in some embodiments, an inhibitoryimmune signal is masked by the present constructs and a stimulatoryimmune signal is activated. Such beneficial properties are enhanced bythe single construct approach of the present chimeric proteins. Forinstance, the signal replacement can be effected nearly simultaneouslyand the signal replacement is tailored to be local at a site of clinicalimportance (e.g. the tumor microenvironment). Further embodiments applythe same principle to other chimeric protein constructs, such as, forexample, (i) the extracellular domain of PD-1 and (ii) extracellulardomain of GITRL; (i) the extracellular domain of BTLA and (ii)extracellular domain of OX40L; (i) the extracellular domain of TIGIT and(ii) extracellular domain of OX40L; (i) the extracellular domain of TIM3and (ii) extracellular domain of OX40L; and (i) the extracellular domainof CD172a and (ii) extracellular domain of CD40L; and (i) theextracellular domain of CD115 and (ii) extracellular domain of CD40L;and (i) the extracellular domain of TIM3 and (ii) extracellular domainof OX40L; and (i) the extracellular domain of TIGIT and (ii)extracellular domain of OX40L; among others.

In various embodiments, the present chimeric proteins are capable of, orfind use in methods comprising, stimulating or enhancing the binding ofimmune stimulatory receptor/ligand pairs. Illustrative T cellcostimulatory receptors and their ligands include OX-40: OX40-L,CD27:CD70, CD30:CD30-L, CD40:CD40-L; CD137:CD137-L, HVEM:LIGHT,GITR:GITR-L, TNFRSF25:TL1A, DR5:TRAIL, and BTLA:HVEM. In variousembodiments, the present chimeric proteins are capable of, or find usein methods comprising, inhibiting or reducing the binding of immuneinhibitory receptor/ligand pairs. Illustrative T cell coinhibitoryreceptors and their ligands include, for example, CTLA-4:CD80/CD86,PD-1:PD-L1/PD-L2, BTLA:HVEM, TIM-3:galectin-9/phosphatidylserine,TIGIT/CD155 or CD112, VISTA/VSIG8, CD172a/CD47, B7H3R/B7H3, B7H4R/B7H4,CD244/CD48, TMIGD2/HHLA2, among others.

In various embodiments, the present chimeric protein blocks, reducesand/or inhibits PD-1 and PD-L1 or PD-L2 and/or the binding of PD-1 withPD-L1 or PD-L2. In various embodiments, the present chimeric proteinblocks, reduces and/or inhibits the activity of CTLA-4 and/or thebinding of CTLA-4 with one or more of AP2M1, CD80, CD86, SHP-2, andPPP2R5A. In various embodiments, the present chimeric protein increasesand/or stimulates GITR and/or the binding of GITR with one or more ofGITR ligand. In various embodiments, the present chimeric proteinincreases and/or stimulates OX40 and/or the binding of OX40 with one ormore of OX40 ligand.

In other embodiments, the present chimeric proteins are capable of, orfind use in methods involving, enhancing, restoring, promoting and/orstimulating immune modulation. In some embodiments, the present chimericproteins described herein, restore, promote and/or stimulate theactivity or activation of one or more immune cells against tumor cellsincluding, but not limited to: T cells, cytotoxic T lymphocytes, Thelper cells, natural killer (NK) cells, natural killer T (NKT) cells,anti-tumor macrophages (e.g. M1 macrophages), B cells, and dendriticcells. In some embodiments, the present chimeric proteins enhance,restore, promote and/or stimulate the activity and/or activation of Tcells, including, by way of a non-limiting example, activating and/orstimulating one or more T-cell intrinsic signals, including apro-survival signal; an autocrine or paracrine growth signal; a p38MAPK-, ERK-, STAT-, JAK-, AKT- or PI3K-mediated signal; ananti-apoptotic signal; and/or a signal promoting and/or necessary forone or more of: proinflammatory cytokine production or T cell migrationor T cell tumor infiltration.

In some embodiments, the present chimeric proteins are capable of, orfind use in methods involving, causing an increase of one or more of Tcells (including without limitation cytotoxic T lymphocytes, T helpercells, natural killer T (NKT) cells), B cells, natural killer (NK)cells, natural killer T (NKT) cells, dendritic cells, monocytes, andmacrophages (e.g. one or more of M1 and M2) into a tumor or the tumormicroenvironment. In some embodiments, the present chimeric proteins arecapable of, or find use in methods involving, inhibiting and/or causinga decrease in recruitment of immunosuppressive cells (e.g.myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs),tumor associated neutrophils (TANs), M2 macrophages, and tumorassociated macrophages (TAMs)) to the tumor and/or tumormicroenvironment (TME). In some embodiments, the present therapies mayalter the ratio of M1 versus M2 macrophages in the tumor site and/or TMEto favor M1 macrophages.

In various embodiments, the present chimeric proteins are capable of,and can be used in methods comprising, inhibiting and/or reducing T cellinactivation and/or immune tolerance to a tumor, comprisingadministering an effective amount of a chimeric protein described hereinto a subject. In some embodiments, the present chimeric proteins areable to increase the serum levels of various cytokines including, butnot limited to, one or more of IFNγ, TNFα, IL-2, IL-4, IL-5, IL-6, IL-9,IL-10, IL-13, IL-17A, IL-17F, and IL-22. In some embodiments, thepresent chimeric proteins are capable of enhancing IL-2, IL-4, IL-5,IL-10, IL-13, IL-17A, IL-22, TNFα or IFNγ in the serum of a treatedsubject (see, e.g. FIG. 11J). Detection of such a cytokine response mayprovide a method to determine the optimal dosing regimen for theindicated chimeric fusion protein (see, e.g. FIG. 11K).

In various embodiments, the present chimeric proteins inhibit, blockand/or reduce cell death of an anti-tumor CD8+ and/or CD4+ T cell; orstimulate, induce, and/or increase cell death of a pro-tumor T cell. Tcell exhaustion is a state of T cell dysfunction characterized byprogressive loss of proliferative and effector functions, culminating inclonal deletion. Accordingly, a pro-tumor T cell refers to a state of Tcell dysfunction that arises during many chronic infections and cancer.This dysfunction is defined by poor proliferative and/or effectorfunctions, sustained expression of inhibitory receptors and atranscriptional state distinct from that of functional effector ormemory T cells. Exhaustion prevents optimal control of infection andtumors. In addition, an anti-tumor CD8+ and/or CD4+ T cell refers to Tcells that can mount an immune response to a tumor. Illustrativepro-tumor T cells include, but are not limited to, Tregs, CD4+ and/orCD8+ T cells expressing one or more checkpoint inhibitory receptors, Th2cells and Th17 cells. Checkpoint inhibitory receptors refers toreceptors (e.g. CTLA-4, B7-H3, B7-H4, TIM-3) expressed on immune cellsthat prevent or inhibit uncontrolled immune responses.

In various embodiments, the present chimeric proteins are capable of,and can be used in methods comprising, increasing a ratio of effector Tcells to regulatory T cells. Illustrative effector T cells include ICOS⁺effector T cells; cytotoxic T cells (e.g. αβ TCR, CD3⁺, CD8⁺, CD45RO⁺);CD4⁺ effector T cells (e.g. αβ TCR, CD3⁺, CD4⁺, CCR7⁺, CD62Lhi,IL-7R/CD127⁺); CD8⁺ effector T cells (e.g. αβ TCR, CD3⁺, CD8+, CCR7⁺,CD62Lhi, IL-7R/CD127⁺); effector memory T cells (e.g. CD62Llow, CD44⁺,TCR, CD3⁺, IL-7R/CD127⁺, IL-15R⁺, CCR7low); central memory T cells (e.g.CCR7⁺, CD62L⁺, CD27⁺; or CCR7hi, CD44⁺, CD62Lhi, TCR, CD3⁺,IL-7R/CD127⁺, IL-15R⁺); CD62L⁺ effector T cells; CD8⁺ effector memory Tcells (TEM) including early effector memory T cells (CD27⁺CD62L−) andlate effector memory T cells (CD27⁻CD62L⁻) (TemE and TemL,respectively); CD127(⁺)CD25(low/−) effector T cells; CD127(⁻)CD25(⁻)effector T cells; CD8⁺ stem cell memory effector cells (TSCM) (e.g.CD44(low)CD62L(high)CD122(high)sca(⁺)); TH1 effector T-cells (e.g.CXCR3⁺, CXCR6⁺ and CCR5⁺; or αβ TCR, CD3⁺, CD4⁺, IL-12R⁺, IFNγR⁺,CXCR3⁺), TH2 effector T cells (e.g. CCR3⁺, CCR4⁺ and CCR8⁺; or αβ TCR,CD3⁺, CD4⁺, IL-4R⁺, IL-33R⁺, CCR4⁺, IL-17RB⁺, CRTH2⁺); TH9 effector Tcells (e.g. αβ TCR, CD3⁺, CD4⁺); TH17 effector T cells (e.g. αβ TCR,CD3⁺, CD4⁺, IL-23R⁺, CCR6⁺, IL-1R⁺); CD4⁺CD45RO⁺CCR7⁺ effector T cells,CD4⁺CD45RO⁺CCR7(⁻) effector T cells; and effector T cells secretingIL-2, IL-4 and/or IFN-γ. Illustrative regulatory T cells include ICOS⁺regulatory T cells, CD4⁺CD25⁺FOXP3⁺ regulatory T cells, CD4⁺CD25⁺regulatory T cells, CD4⁺CD25⁻ regulatory T cells, CD4⁺CD25highregulatory T cells, TIM-3⁺PD-1⁺ regulatory T cells, lymphocyteactivation gene-3 (LAG-3)⁺ regulatory T cells, CTLA-4/CD152⁺ regulatoryT cells, neuropilin-1 (Nrp-1)⁺ regulatory T cells, CCR4⁺CCR8⁺ regulatoryT cells, CD62L (L-selectin)⁺ regulatory T cells, CD45RBlow regulatory Tcells, CD127low regulatory T cells, LRRC32/GARP⁺ regulatory T cells,CD39⁺ regulatory T cells, GITR⁺ regulatory T cells, LAP⁺ regulatory Tcells, 1B11⁺ regulatory T cells, BTLA⁺ regulatory T cells, type 1regulatory T cells (Tr1 cells), T helper type 3 (Th3) cells, regulatorycell of natural killer T cell phenotype (NKTregs), CD8⁺ regulatory Tcells, CD8⁺CD28⁻ regulatory T cells and/or regulatory T-cells secretingIL-10, IL-35, TGF-β, TNF-α, Galectin-1, IFN-γ and/or MCP1.

In various embodiments, the present chimeric proteins are capable of,and can be used in methods comprising, transiently stimulating effectorT cells for no longer than about 12 hours, about 24 hours, about 48hours, about 72 hours or about 96 hours or about 1 week or about 2weeks. In various embodiments, the present chimeric proteins are capableof, and can be used in methods comprising, transiently depleting orinhibiting regulatory T cells for no longer than about 12 hours, about24 hours, about 48 hours, about 72 hours or about 96 hours or about 1week or about 2 weeks. In various embodiments, the transient stimulationof effector T cells and/or transient depletion or inhibition ofregulatory T cells occurs substantially in a patient's bloodstream or ina particular tissue/location including lymphoid tissues such as forexample, the bone marrow, lymph-node, spleen, thymus, mucosa-associatedlymphoid tissue (MALT), non-lymphoid tissues, or in the tumormicroenvironment.

In various embodiments, the present chimeric proteins provide advantagesincluding, without limitation, ease of use and ease of production. Thisis because two distinct immunotherapy agents are combined into a singleproduct which allows for a single manufacturing process instead of twoindependent manufacturing processes. In addition, administration of asingle agent instead of two separate agents allows for easieradministration and greater patient compliance. Further, in contrast to,for example, monoclonal antibodies, which are large multimeric proteinscontaining numerous disulfide bonds and post-translational modificationssuch as glycosylation, the present chimeric proteins are easier and morecost effective to manufacture.

In various embodiments, the present chimeric protein is produceable in amammalian host cell as a secretable and fully functional singlepolypeptide chain (see, e.g., FIG. 13A, FIG. 17E to FIG. 17H, FIG. 17Nto FIG. 17S).

In various embodiments, the present chimeric protein unexpectedlyprovides binding of the extracellular domain components to theirrespective binding partners with slow off rates (Kd or K_(off)). In someembodiments, this provides an unexpectedly long interaction of thereceptor to ligand and vice versa. Such an effect allows for a sustainednegative signal masking effect (see, e.g., FIG. 14A to FIG. 14L, FIG.17I to FIG. 17M). Further, in some embodiments, this delivers a longerpositive signal effect, e.g. to allow an effector cell to be adequatelystimulated for an anti-tumor effect. For example, the present chimericprotein, e.g. via the long off rate binding allows sufficient signaltransmission to provide T cell proliferation and allow for anti-tumorattack. By way of further example, the present chimeric protein, e.g.via the long off rate binding allows sufficient signal transmission toprovide release of stimulatory signals, such as, for example, cytokinesAlso. The stable synapse of cells promoted by the present agents (e.g. atumor cell bearing negative signals and a T cell which could attack thetumor) provides spatial orientation to favor tumor reduction—such aspositioning the T cells to attack tumor cells and/or stericallypreventing the tumor cell from delivering negative signals, includingnegative signals beyond those masked by the chimeric protein of theinvention.

In some embodiments, this provides longer on-target (e.g. intra-tumoral)half-life (t_(1/2)) as compared to serum t₁/2 of the chimeric proteins.Such properties could have the combined advantage of reducing off-targettoxicities associated with systemic distrubition of the chimericproteins (see, e.g., FIG. 14M to FIG. 14O).

Further, in various embodiments, the present chimeric proteins providesynergistic therapeutic effects as it allows for improved site-specificinterplay of two immunotherapy agents. In some embodiments, the presentchimeric proteins provide the potential for reducing off-site and/orsystemic toxicity.

Diseases; Methods of Treatment, and Patient Selections

In various embodiments, the present invention pertains to cancers and/ortumors; for example, the treatment or prevention of cancers and/ortumors. As described elsewhere herein, the treatment of cancer mayinvolve in various embodiments, modulating the immune system with thepresent chimeric proteins to favor immune stimulation over immuneinhibition.

Cancers or tumors refer to an uncontrolled growth of cells and/orabnormal increased cell survival and/or inhibition of apoptosis whichinterferes with the normal functioning of the bodily organs and systems.Included are benign and malignant cancers, polyps, hyperplasia, as wellas dormant tumors or micrometastases. Also, included are cells havingabnormal proliferation that is not impeded by the immune system (e.g.virus infected cells). The cancer may be a primary cancer or ametastatic cancer. The primary cancer may be an area of cancer cells atan originating site that becomes clinically detectable, and may be aprimary tumor. In contrast, the metastatic cancer may be the spread of adisease from one organ or part to another non-adjacent organ or part.The metastatic cancer may be caused by a cancer cell that acquires theability to penetrate and infiltrate surrounding normal tissues in alocal area, forming a new tumor, which may be a local metastasis. Thecancer may also be caused by a cancer cell that acquires the ability topenetrate the walls of lymphatic and/or blood vessels, after which thecancer cell is able to circulate through the bloodstream (thereby beinga circulating tumor cell) to other sites and tissues in the body. Thecancer may be due to a process such as lymphatic or hematogeneousspread. The cancer may also be caused by a tumor cell that comes to restat another site, re-penetrates through the vessel or walls, continues tomultiply, and eventually forms another clinically detectable tumor. Thecancer may be this new tumor, which may be a metastatic (or secondary)tumor.

The cancer may be caused by tumor cells that have metastasized, whichmay be a secondary or metastatic tumor. The cells of the tumor may belike those in the original tumor. As an example, if a breast cancer orcolon cancer metastasizes to the liver, the secondary tumor, whilepresent in the liver, is made up of abnormal breast or colon cells, notof abnormal liver cells. The tumor in the liver may thus be a metastaticbreast cancer or a metastatic colon cancer, not liver cancer.

The cancer may have an origin from any tissue. The cancer may originatefrom melanoma, colon, breast, or prostate, and thus may be made up ofcells that were originally skin, colon, breast, or prostate,respectively. The cancer may also be a hematological malignancy, whichmay be leukemia or lymphoma. The cancer may invade a tissue such asliver, lung, bladder, or intestinal.

Representative cancers and/or tumors of the present invention include,but are not limited to, a basal cell carcinoma, biliary tract cancer;bladder cancer; bone cancer; brain and central nervous system cancer;breast cancer; cancer of the peritoneum; cervical cancer;choriocarcinoma; colon and rectum cancer; connective tissue cancer;cancer of the digestive system; endometrial cancer; esophageal cancer;eye cancer; cancer of the head and neck; gastric cancer (includinggastrointestinal cancer); glioblastoma; hepatic carcinoma; hepatoma;intra-epithelial neoplasm; kidney or renal cancer; larynx cancer;leukemia; liver cancer; lung cancer (e.g., small-cell lung cancer,non-small cell lung cancer, adenocarcinoma of the lung, and squamouscarcinoma of the lung); melanoma; myeloma; neuroblastoma; oral cavitycancer (lip, tongue, mouth, and pharynx); ovarian cancer; pancreaticcancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectalcancer; cancer of the respiratory system; salivary gland carcinoma;sarcoma; skin cancer; squamous cell cancer; stomach cancer; testicularcancer; thyroid cancer; uterine or endometrial cancer; cancer of theurinary system; vulval cancer; lymphoma including Hodgkin's andnon-Hodgkin's lymphoma, as well as B-cell lymphoma (including lowgrade/follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL)NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL;high grade immunoblastic NHL; high grade lymphoblastic NHL; high gradesmall non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma;AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia; chroniclymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairycell leukemia; chronic myeloblastic leukemia; as well as othercarcinomas and sarcomas; and post-transplant lymphoproliferativedisorder (PTLD), as well as abnormal vascular proliferation associatedwith phakomatoses, edema (such as that associated with brain tumors),and Meigs' syndrome.

In some embodiments, the chimeric protein is used to treat a subjectthat has a treatment-refractory cancer. In some embodiments, thechimeric protein is used to treat a subject that is refractory to one ormore immune-modulating agents. For example, in some embodiments, thechimeric protein is used to treat a subject that presents no response totreatment, or even progress, after 12 weeks or so of treatment. Forinstance, in some embodiments, the subject is refractory to a PD-1and/or PD-L1 and/or PD-L2 agent, including, for example, nivolumab(ONO-4538/BMS-936558, MDX1106, OPDIVO, BRISTOL MYERS SQUIBB),pembrolizumab (KEYTRUDA, MERCK), pidilizumab (CT-011, CURE TECH),MK-3475 (MERCK), BMS 936559 (BRISTOL MYERS SQUIBB), Ibrutinib(PHARMACYCLICS/ABBVIE), atezolizumab (TECENTRIQ, GENENTECH), and/orMPDL3280A (ROCHE)-refractory patients. For instance, in someembodiments, the subject is refractory to an anti-CTLA-4 agent, e.g.ipilimumab (YERVOY)-refractory patients (e.g. melanoma patients).Accordingly, in various embodiments the present invention providesmethods of cancer treatment that rescue patients that are non-responsiveto various therapies, including monotherapy of one or moreimmune-modulating agents.

In some embodiments, the present methods provide treatment with thechimeric protein in a patient who is refractory to an additional agent,such “additional agents” being described elsewhere herein, inclusive,without limitation, of the various chemotherapeutic agents describedherein.

In some aspects, the present chimeric agents are used to eliminateintracellular pathogens. In some aspects, the present chimeric agentsare used to treat one or more infections. In some embodiments, thepresent chimeric proteins are used in methods of treating viralinfections (including, for example, HIV and HCV), parasitic infections(including, for example, malaria), and bacterial infections. In variousembodiments, the infections induce immunosuppression. For example, HIVinfections often result in immunosuppression in the infected subjects.Accordingly, as described elsewhere herein, the treatment of suchinfections may involve, in various embodiments, modulating the immunesystem with the present chimeric proteins to favor immune stimulationover immune inhibition. Alternatively, the present invention providesmethods for treating infections that induce immunoactivation. Forexample, intestinal helminth infections have been associated withchronic immune activation. In these embodiments, the treatment of suchinfections may involve modulating the immune system with the presentchimeric proteins to favor immune inhibition over immune stimulation.

In various embodiments, the present invention provides methods oftreating viral infections including, without limitation, acute orchronic viral infections, for example, of the respiratory tract, ofpapilloma virus infections, of herpes simplex virus (HSV) infection, ofhuman immunodeficiency virus (HIV) infection, and of viral infection ofinternal organs such as infection with hepatitis viruses. In someembodiments, the viral infection is caused by a virus of familyFlaviviridae. In some embodiments, the virus of family Flaviviridae isselected from Yellow Fever Virus, West Nile virus, Dengue virus,Japanese Encephalitis Virus, St. Louis Encephalitis Virus, and HepatitisC Virus. In other embodiments, the viral infection is caused by a virusof family Picornaviridae, e.g., poliovirus, rhinovirus, coxsackievirus.In other embodiments, the viral infection is caused by a member ofOrthomyxoviridae, e.g., an influenza virus. In other embodiments, theviral infection is caused by a member of Retroviridae, e.g., alentivirus. In other embodiments, the viral infection is caused by amember of Paramyxoviridae, e.g., respiratory syncytial virus, a humanparainfluenza virus, rubulavirus (e.g., mumps virus), measles virus, andhuman metapneumovirus. In other embodiments, the viral infection iscaused by a member of Bunyaviridae, e.g., hantavirus. In otherembodiments, the viral infection is caused by a member of Reoviridae,e.g., a rotavirus.

In various embodiments, the present invention provides methods oftreating parasitic infections such as protozoan or helminths infections.In some embodiments, the parasitic infection is by a protozoan parasite.In some embodiments, the oritiziab parasite is selected from intestinalprotozoa, tissue protozoa, or blood protozoa. Illustrative protozoanparasites include, but are not limited to, Entamoeba hystolytica,Giardia lamblia, Cryptosporidium muris, Trypanosomatida gambiense,Trypanosomatida rhodesiense, Trypanosomatida crusi, Leishmania mexicana,Leishmania braziliensis, Leishmania tropica, Leishmania donovani,Toxoplasma gondii, Plasmodium vivax, Plasmodium ovale, Plasmodiummalariae, Plasmodium falciparum, Trichomonas vaginalis, and Histomonasmeleagridis. In some embodiments, the parasitic infection is by ahelminthic parasite such as nematodes (e.g., Adenophorea). In someembodiments, the parasite is selected from Secementea (e.g., Trichuristrichiura, Ascaris lumbricoides, Enterobius vermicularis, Ancylostomaduodenale, Necator americanus, Strongyloides stercoralis, Wuchereriabancrofti, Dracunculus medinensis). In some embodiments, the parasite isselected from trematodes (e.g. blood flukes, liver flukes, intestinalflukes, and lung flukes). In some embodiments, the parasite is selectedfrom: Schistosoma mansoni, Schistosoma haematobium, Schistosomajaponicum, Fasciola hepatica, Fasciola gigantica, Heterophyesheterophyes, Paragonimus westermani. In some embodiments, the parasiteis selected from cestodes (e.g., Taenia solium, Taenia saginata,Hymenolepis nana, Echinococcus granulosus).

In various embodiments, the present invention provides methods oftreating bacterial infections. In various embodiments, the bacterialinfection is by a gram-positive bacteria, gram-negative bacteria,aerobic and/or anaerobic bacteria. In various embodiments, the bacteriais selected from, but not limited to, Staphylococcus, Lactobacillus,Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella,Pseudomonas, Acinetobacter, Mycobacterium, Proteus, Campylobacter,Citrobacter, Nisseria, Baccillus, Bacteroides, Peptococcus, Clostridium,Salmonella, Shigella, Serratia, Haemophilus, Brucella and otherorganisms. In some embodiments, the bacteria is selected from, but notlimited to, Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonasacidovorans, Pseudomonas alcaligenes, Pseudomonas putida,Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonashydrophilia, Escherichia coli, Citrobacter freundii, Salmonellatyphimurium, Salmonella typhi, Salmonella paratyphi, Salmonellaenteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei,Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae,Klebsiella oxytoca, Serratia marcescens, Francisella tularensis,Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providenciaalcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacterbaumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus,Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis,Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis,Bordetella bronchiseptica, Haemophilus influenzae, Haemophilusparainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus,Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica,Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus,Campylobacterjejuni, Campylobacter coli, Borrelia burgdorferi, Vibriocholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeriamonocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella,Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroidesdistasonis, Bacteroides 3452A homology group, Bacteroides vulgatus,Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis,Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile,Mycobacterium tuberculosis, Mycobacterium avium, Mycobacteriumintracellulare, Mycobacterium leprae, Corynebacterium diphtheriae,Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcusagalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcusfaecium, Staphylococcus aureus, Staphylococcus epidermidis,Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcushyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcushominis, or Staphylococcus saccharolyticus.

In some aspects, the present chimeric agents are used to treat one ormore autoimmune diseases or disorders. In various embodiments, thetreatment of an autoimmune disease or disorder may involve modulatingthe immune system with the present chimeric proteins to favor immuneinhibition over immune stimulation. Illustrative autoimmune diseases ordisorders treatable with the present chimeric proteins include those inwhich the body's own antigens become targets for an immune response,such as, for example, rheumatoid arthritis, systemic lupuserythematosus, diabetes mellitus, ankylosing spondylitis, Sjögren'ssyndrome, inflammatory bowel diseases (e.g. colitis ulcerosa, Crohn'sdisease), multiple sclerosis, sarcoidosis, psoriasis, Grave's disease,Hashimoto's thyroiditis, psoriasis, hypersensitivity reactions (e.g.,allergies, hay fever, asthma, and acute edema cause type Ihypersensitivity reactions), and vasculitis.

In still another other aspect, the present invention is directed towardmethods of treating and preventing T cell-mediated diseases anddisorders, such as, but not limited to diseases or disorders describedelsewhere herein and inflammatory disease or disorder, graft-versus-hostdisease (GVHD), transplant rejection, and T cell proliferative disorder.Specific examples of type I ECD domains with utility in this method ofuse include but are not limited to: TNFRSF1b, BTNL2, PD-L1, PD-L2,CTLA-4, B7-H3, B7-H4, CD40, OX40, CD137, among others.

In some aspects, the present chimeric agents are used in methods ofactivating a T cell, e.g. via the extracellular domain having an immunestimulatory signal.

In some aspects, the present chimeric agents are used in methods ofpreventing the cellular transmission of an immunosuppressive signal.

Combination Therapies and Conjugation

In some embodiments, the invention provides for chimeric proteins andmethods that further comprise administering an additional agent to asubject. In some embodiments, the invention pertains toco-administration and/or co-formulation. Any of the compositionsdescribed herein may be co-formulated and/or co-administered.

In some embodiments, any chimeric protein described herein actssynergistically when co-administered with another agent and isadministered at doses that are lower than the doses commonly employedwhen such agents are used as monotherapy. In various embodiments, anyagent referenced herein may be used in combination with any of thechimeric proteins described herein.

In some embodiments, inclusive of, without limitation, cancerapplications, the present invention pertains to chemotherapeutic agentsas additional agents. Examples of chemotherapeutic agents include, butare not limited to, alkylating agents such as thiotepa and CYTOXANcyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan andpiposulfan; aziridines such as benzodopa, carboquone, meturedopa, anduredopa; ethylenimines and methylamelamines including altretamine,triethylenemelamine, trietylenephosphoramide,triethiylenethiophosphoramide and trimethylolomelamine; acetogenins(e.g., bullatacin and bullatacinone); a camptothecin (including thesynthetic analogue topotecan); bryostatin; cally statin; CC-1065(including its adozelesin, carzelesin and bizelesin syntheticanalogues); cryptophycins (e.g., cryptophycin 1 and cryptophycin 8);dolastatin; duocarmycin (including the synthetic analogues, KW-2189 andCB 1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin;nitrogen mustards such as chlorambucil, chlornaphazine,cholophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureassuch as carmustine, chlorozotocin, fotemustine, lomustine, nimustine,and ranimnustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, especially calicheamicin gammall and calicheamicinomegall (see, e.g., Agnew, Chem. Intl. Ed. Engl., 33: 183-186 (1994));dynemicin, including dynemicin A; bisphosphonates, such as clodronate;an esperamicin; as well as neocarzinostatin chromophore and relatedchromoprotein enediyne antibiotic chromophores), aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCINdoxorubicin (including morpholino-doxorubicin,cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin,mitomycins such as mitomycin C, mycophenolic acid, nogalamycin,olivomycins, peplomycin, potfiromycin, puromycin, quelamycin,rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex,zinostatin, zorubicin; anti-metabolites such as methotrexate and5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as minoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; demecolcine; diaziquone;elformithine; elliptinium acetate; an epothilone; etoglucid; galliumnitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such asmaytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine; trichothecenes (e.g., T-2 toxin, verracurinA, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOLpaclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANECremophor-free, albumin-engineered nanoparticle formulation ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), andTAXOTERE doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil;GEMZAR gemcitabine; 6-thioguanine; mercaptopurine; methotrexate;platinum analogs such as cisplatin, oxaliplatin and carboplatin;vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone;vincristine; NAVELBINE. vinorelbine; novantrone; teniposide; edatrexate;daunomycin; aminopterin; xeloda; ibandronate; irinotecan (Camptosar,CPT-11) (including the treatment regimen of irinotecan with 5-FU andleucovorin); topoisomerase inhibitor RFS 2000; difluoromethylornithine(DMFO); retinoids such as retinoic acid; capecitabine; combretastatin;leucovorin (LV); oxaliplatin, including the oxaliplatin treatmentregimen (FOLFOX); lapatinib (TYKERB); inhibitors of PKC-α, Raf, H-Ras,EGFR (e.g., erlotinib (Tarceva)) and VEGF-A that reduce cellproliferation and pharmaceutically acceptable salts, acids orderivatives of any of the above. In addition, the methods of treatmentcan further include the use of radiation. In addition, the methods oftreatment can further include the use of photodynamic therapy.

In various embodiments, inclusive of, without limitation, cancerapplications, the present additional agent is one or moreimmune-modulating agents selected from an agent that blocks, reducesand/or inhibits PD-1 and PD-L1 or PD-L2 and/or the binding of PD-1 withPD-L1 or PD-L2 (by way of non-limiting example, one or more of nivolumab(ONO-4538/BMS-936558, MDX1106, OPDIVO, BRISTOL MYERS SQUIBB),pembrolizumab (KEYTRUDA, Merck), pidilizumab (CT-011, CURE TECH),MK-3475 (MERCK), BMS 936559 (BRISTOL MYERS SQUIBB), atezolizumab(TECENTRIQ, GENENTECH), MPDL328OA (ROCHE)), an agent that increasesand/or stimulates CD137 (4-1BB) and/or the binding of CD137 (4-1BB) withone or more of 4-1BB ligand (by way of non-limiting example, urelumab(BMS-663513 and anti-4-1BB antibody), and an agent that blocks, reducesand/or inhibits the activity of CTLA-4 and/or the binding of CTLA-4 withone or more of AP2M1, CD80, CD86, SHP-2, and PPP2R5A and/or the bindingof OX40 with OX40L (by way of non-limiting example GBR 830 (GLENMARK),MED16469 (MEDIMMUNE).

In some embodiments, inclusive of, without limitation, infectiousdisease applications, the present invention pertains to anti-infectivesas additional agents. In some embodiments, the anti-infective is ananti-viral agent including, but not limited to, Abacavir, Acyclovir,Adefovir, Amprenavir, Atazanavir, Cidofovir, Darunavir, Delavirdine,Didanosine, Docosanol, Efavirenz, Elvitegravir, Emtricitabine,Enfuvirtide, Etravirine, Famciclovir, and Foscarnet. In someembodiments, the anti-infective is an anti-bacterial agent including,but not limited to, cephalosporin antibiotics (cephalexin, cefuroxime,cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin,cefprozil, and ceftobiprole); fluoroquinolone antibiotics (cipro,Levaquin, floxin, tequin, avelox, and norflox); tetracycline antibiotics(tetracycline, minocycline, oxytetracycline, and doxycycline);penicillin antibiotics (amoxicillin, ampicillin, penicillin V,dicloxacillin, carbenicillin, vancomycin, and methicillin); monobactamantibiotics (aztreonam); and carbapenem antibiotics (ertapenem,doripenem, imipenem/cilastatin, and meropenem). In some embodiments, theanti-infectives include anti-malarial agents (e.g., chloroquine,quinine, mefloquine, primaquine, doxycycline, artemether/lumefantrine,atovaquone/proguanil and sulfadoxine/pyrimethamine), metronidazole,tinidazole, ivermectin, pyrantel pamoate, and albendazole.

In some embodiments, inclusive, without limitation, of autoimmuneapplications, the additional agent is an immunosuppressive agent. Insome embodiments, the immunosuppressive agent is an anti-inflammatoryagent such as a steroidal anti-inflammatory agent or a non-steroidalanti-inflammatory agent (NSAID). Steroids, particularly the adrenalcorticosteroids and their synthetic analogues, are well known in theart. Examples of corticosteroids useful in the present inventioninclude, without limitation, hydroxyltriamcinolone, alpha-methyldexamethasone, beta-methyl betamethasone, beclomethasone dipropionate,betamethasone benzoate, betamethasone dipropionate, betamethasonevalerate, clobetasol valerate, desonide, desoxymethasone, dexamethasone,diflorasone diacetate, diflucortolone valerate, fluadrenolone,fluclorolone acetonide, flumethasone pivalate, fluosinolone acetonide,fluocinonide, flucortine butylester, fluocortolone, fluprednidene(fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisoneacetate, hydrocortisone butyrate, methylprednisolone, triamcinoloneacetonide, cortisone, cortodoxone, flucetonide, fludrocortisone,difluorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel,amcinafide, betamethasone and the balance of its esters,chloroprednisone, clocortelone, clescinolone, dichlorisone,difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone,fluprednisolone, hydrocortisone, meprednisone, paramethasone,prednisolone, prednisone, beclomethasone dipropionate. (NSAIDS) that maybe used in the present invention, include but are not limited to,salicylic acid, acetyl salicylic acid, methyl salicylate, glycolsalicylate, salicylmides, benzyl-2,5-diacetoxybenzoic acid, ibuprofen,fulindac, naproxen, ketoprofen, etofenamate, phenylbutazone, andindomethacin. In some embodiments, the immunosupressive agent may becytostatics such as alkylating agents, antimetabolites (e.g.,azathioprine, methotrexate), cytotoxic antibiotics, antibodies (e.g.,basiliximab, daclizumab, and muromonab), anti-immunophilins (e.g.,cyclosporine, tacrolimus, sirolimus), inteferons, opioids, TNF bindingproteins, mycophenolates, and small biological agents (e.g., fingolimod,myriocin).

In some embodiments, the chimeric proteins (and/or additional agents)described herein, include derivatives that are modified, i.e., by thecovalent attachment of any type of molecule to the composition such thatcovalent attachment does not prevent the activity of the composition.For example, but not by way of limitation, derivatives includecomposition that have been modified by, inter alia, glycosylation,lipidation, acetylation, pegylation, phosphorylation, amidation,derivatization by known protecting/blocking groups, proteolyticcleavage, linkage to a cellular ligand or other protein, etc. Any ofnumerous chemical modifications can be carried out by known techniques,including, but not limited to specific chemical cleavage, acetylation,formylation, metabolic synthesis of turicamycin, etc. Additionally, thederivative can contain one or more non-classical amino acids. In stillother embodiments, the chimeric proteins (and/or additional agents)described herein further comprise a cytotoxic agent, comprising, inillustrative embodiments, a toxin, a chemotherapeutic agent, aradioisotope, and an agent that causes apoptosis or cell death. Suchagents may be conjugated to a composition described herein.

The chimeric proteins (and/or additional agents) described herein maythus be modified post-translationally to add effector moieties such aschemical linkers, detectable moieties such as for example fluorescentdyes, enzymes, substrates, bioluminescent materials, radioactivematerials, and chemiluminescent moieties, or functional moieties such asfor example streptavidin, avidin, biotin, a cytotoxin, a cytotoxicagent, and radioactive materials.

Formulations

The chimeric proteins (and/or additional agents) described herein canpossess a sufficiently basic functional group, which can react with aninorganic or organic acid, or a carboxyl group, which can react with aninorganic or organic base, to form a pharmaceutically acceptable salt. Apharmaceutically acceptable acid addition salt is formed from apharmaceutically acceptable acid, as is well known in the art. Suchsalts include the pharmaceutically acceptable salts listed in, forexample, Journal of Pharmaceutical Science, 66, 2-19 (1977) and TheHandbook of Pharmaceutical Salts; Properties, Selection, and Use. P. H.Stahl and C. G. Wermuth (eds.), Verlag, Zurich (Switzerland) 2002, whichare hereby incorporated by reference in their entirety.

In some embodiments, the compositions described herein are in the formof a pharmaceutically acceptable salt.

Further, any chimeric protein (and/or additional agents) describedherein can be administered to a subject as a component of a compositionthat comprises a pharmaceutically acceptable carrier or vehicle. Suchcompositions can optionally comprise a suitable amount of apharmaceutically acceptable excipient so as to provide the form forproper administration. Pharmaceutical excipients can be liquids, such aswater and oils, including those of petroleum, animal, vegetable, orsynthetic origin, such as peanut oil, soybean oil, mineral oil, sesameoil and the like. The pharmaceutical excipients can be, for example,saline, gum acacia, gelatin, starch paste, talc, keratin, colloidalsilica, urea and the like. In addition, auxiliary, stabilizing,thickening, lubricating, and coloring agents can be used. In oneembodiment, the pharmaceutically acceptable excipients are sterile whenadministered to a subject. Water is a useful excipient when any agentdescribed herein is administered intravenously. Saline solutions andaqueous dextrose and glycerol solutions can also be employed as liquidexcipients, specifically for injectable solutions. Suitablepharmaceutical excipients also include starch, glucose, lactose,sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate,glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol,propylene, glycol, water, ethanol and the like. Any agent describedherein, if desired, can also comprise minor amounts of wetting oremulsifying agents, or pH buffering agents.

In some embodiments, the compositions described herein are resuspendedin a saline buffer (including, without limitation TBS, PBS, and thelike).

In various embodiments, the chimeric proteins may by conjugated and/orfused with another agent to extend half-life or otherwise improvepharmacodynamic and pharmacokinetic properties. In some embodiments, thechimeric proteins may be fused or conjugated with one or more of PEG,XTEN (e.g., as rPEG), polysialic acid (POLYXEN), albumin (e.g., humanserum albumin or HAS), elastin-like protein (ELP), PAS, HAP, GLK, CTP,transferrin, and the like. In various embodiments, each of theindividual chimeric proteins is fused to one or more of the agentsdescribed in BioDrugs (2015) 29:215-239, the entire contents of whichare hereby incorporated by reference.

Administration, Dosing, and Treatment Regimens

The present invention includes the described chimeric protein (and/oradditional agents) in various formulations. Any chimeric protein (and/oradditional agents) described herein can take the form of solutions,suspensions, emulsion, drops, tablets, pills, pellets, capsules,capsules containing liquids, powders, sustained-release formulations,suppositories, emulsions, aerosols, sprays, suspensions, or any otherform suitable for use. DNA or RNA constructs encoding the proteinsequences may also be used. In one embodiment, the composition is in theform of a capsule (see, e.g., U.S. Pat. No. 5,698,155). Other examplesof suitable pharmaceutical excipients are described in Remington'sPharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed.1995), incorporated herein by reference.

Where necessary, the formulations comprising the chimeric protein(and/or additional agents) can also include a solubilizing agent. Also,the agents can be delivered with a suitable vehicle or delivery deviceas known in the art. Combination therapies outlined herein can beco-delivered in a single delivery vehicle or delivery device.Compositions for administration can optionally include a localanesthetic such as, for example, lignocaine to lessen pain at the siteof the injection.

The formulations comprising the chimeric protein (and/or additionalagents) of the present invention may conveniently be presented in unitdosage forms and may be prepared by any of the methods well known in theart of pharmacy. Such methods generally include the step of bringing thetherapeutic agents into association with a carrier, which constitutesone or more accessory ingredients. Typically, the formulations areprepared by uniformly and intimately bringing the therapeutic agent intoassociation with a liquid carrier, a finely divided solid carrier, orboth, and then, if necessary, shaping the product into dosage forms ofthe desired formulation (e.g., wet or dry granulation, powder blends,etc., followed by tableting using conventional methods known in the art)

In one embodiment, any chimeric protein (and/or additional agents)described herein is formulated in accordance with routine procedures asa composition adapted for a mode of administration described herein.

Routes of administration include, for example: intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intranasal, intracerebral, intravaginal,transdermal, rectally, by inhalation, or topically, particularly to theears, nose, eyes, or skin. In some embodiments, the administering iseffected orally or by parenteral injection. In most instances,administration results in the release of any agent described herein intothe bloodstream.

Any chimeric protein (and/or additional agents) described herein can beadministered orally. Such chimeric proteins (and/or additional agents)can also be administered by any other convenient route, for example, byintravenous infusion or bolus injection, by absorption throughepithelial or mucocutaneous linings (e.g., oral mucosa, rectal andintestinal mucosa, etc.) and can be administered together with anotherbiologically active agent. Administration can be systemic or local.Various delivery systems are known, e.g., encapsulation in liposomes,microparticles, microcapsules, capsules, etc., and can be used toadminister.

In specific embodiments, it may be desirable to administer locally tothe area in need of treatment. In one embodiment, for instance in thetreatment of cancer, the chimeric protein (and/or additional agents) areadministered in the tumor microenvironment (e.g. cells, molecules,extracellular matrix and/or blood vessels that surround and/or feed atumor cell, inclusive of, for example, tumor vasculature;tumor-infiltrating lymphocytes; fibroblast reticular cells; endothelialprogenitor cells (EPC); cancer-associated fibroblasts; pericytes; otherstromal cells; components of the extracellular matrix (ECM); dendriticcells; antigen presenting cells; T-cells; regulatory T cells;macrophages; neutrophils; and other immune cells located proximal to atumor) or lymph node and/or targeted to the tumor microenvironment orlymph node. In various embodiments, for instance in the treatment ofcancer, the chimeric protein (and/or additional agents) are administeredintratumorally.

In the various embodiments, the present chimeric protein allows for adual effect that provides less side effects than are seen inconventional immunotherapy (e.g. treatments with one or more of OPDIVO,KEYTRUDA, YERVOY, and TECENTRIQ). For example, the present chimericproteins reduce or prevent commonly observed immune-related adverseevents that affect various tissues and organs including the skin, thegastrointestinal tract, the kidneys, peripheral and central nervoussystem, liver, lymph nodes, eyes, pancreas, and the endocrine system;such as hypophysitis, colitis, hepatitis, pneumonitis, rash, andrheumatic disease. Further, the present local administration, e.g.intratumorally, obviate adverse event seen with standard systemicadministration, e.g. IV infusions, as are used with conventionalimmunotherapy (e.g. treatments with one or more of OPDIVO, KEYTRUDA,YERVOY, and TECENTRIQ).

Dosage forms suitable for parenteral administration (e.g. intravenous,intramuscular, intraperitoneal, subcutaneous and intra-articularinjection and infusion) include, for example, solutions, suspensions,dispersions, emulsions, and the like. They may also be manufactured inthe form of sterile solid compositions (e.g. lyophilized composition),which can be dissolved or suspended in sterile injectable mediumimmediately before use. They may contain, for example, suspending ordispersing agents known in the art.

The dosage of any chimeric protein (and/or additional agents) describedherein as well as the dosing schedule can depend on various parameters,including, but not limited to, the disease being treated, the subject'sgeneral health, and the administering physician's discretion. Anychimeric protein described herein, can be administered prior to (e.g., 5minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before),concurrently with, or subsequent to (e.g., 5 minutes, 15 minutes, 30minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks,5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of anadditional agent, to a subject in need thereof. In various embodimentsany chimeric protein and additional agent described herein areadministered 1 minute apart, 10 minutes apart, 30 minutes apart, lessthan 1 hour apart, 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hoursto 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hoursapart, 11 hours to 12 hours apart, no more than 24 hours apart or nomore than 48 hours apart.

The dosage of any chimeric protein (and/or additional agents) describedherein can depend on several factors including the severity of thecondition, whether the condition is to be treated or prevented, and theage, weight, and health of the subject to be treated. Additionally,pharmacogenomic (the effect of genotype on the pharmacokinetic,pharmacodynamic or efficacy profile of a therapeutic) information abouta particular subject may affect dosage used. Furthermore, the exactindividual dosages can be adjusted somewhat depending on a variety offactors, including the specific combination of the agents beingadministered, the time of administration, the route of administration,the nature of the formulation, the rate of excretion, the particulardisease being treated, the severity of the disorder, and the anatomicallocation of the disorder. Some variations in the dosage can be expected.

For administration of any chimeric protein (and/or additional agents)described herein by parenteral injection, the dosage is normally 0.1 mgto 250 mg per day, 1 mg to 20 mg per day, or 3 mg to 5 mg per day.Injections may be given up to four times daily. Generally, when orallyor parenterally administered, the dosage of any agent described hereinis normally 0.1 mg to 1500 mg per day, or 0.5 mg to 10 mg per day, or0.5 mg to 5 mg per day. A dosage of up to 3000 mg per day can beadministered.

In another embodiment, delivery can be in a vesicle, in particular aliposome (see Langer, 1990, Science 249:1527-1533; Treat et al., inLiposomes in the Therapy of Infectious Disease and Cancer,Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989).

Any chimeric protein (and/or additional agents) described herein can beadministered by controlled-release or sustained-release means or bydelivery devices that are well known to those of ordinary skill in theart. Examples include, but are not limited to, those described in U.S.Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719;5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476;5,354,556; and 5,733,556, each of which is incorporated herein byreference in its entirety. Such dosage forms can be useful for providingcontrolled- or sustained-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Controlled-or sustained-release of an active ingredient can be stimulated byvarious conditions, including but not limited to, changes in pH, changesin temperature, stimulation by an appropriate wavelength of light,concentration or availability of enzymes, concentration or availabilityof water, or other physiological conditions or compounds.

In another embodiment, polymeric materials can be used (see MedicalApplications of Controlled Release, Langer and Wise (eds.), CRC Pres.,Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug ProductDesign and Performance, Smolen and Ball (eds.), Wiley, New York (1984);Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61;see also Levy et al., 1985, Science 228:190; During et al., 1989, Ann.Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105).

In another embodiment, a controlled-release system can be placed inproximity of the target area to be treated, thus requiring only afraction of the systemic dose (see, e.g., Goodson, in MedicalApplications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).Other controlled-release systems discussed in the review by Langer,1990, Science 249:1527-1533) may be used.

Administration of any chimeric protein (and/or additional agents)described herein can, independently, be one to four times daily or oneto four times per month or one to six times per year or once every two,three, four or five years. Administration can be for the duration of oneday or one month, two months, three months, six months, one year, twoyears, three years, and may even be for the life of the subject.

The dosage regimen utilizing any chimeric protein (and/or additionalagents) described herein can be selected in accordance with a variety offactors including type, species, age, weight, sex and medical conditionof the subject; the severity of the condition to be treated; the routeof administration; the renal or hepatic function of the subject; thepharmacogenomic makeup of the individual; and the specific compound ofthe invention employed. Any chimeric protein (and/or additional agents)described herein can be administered in a single daily dose, or thetotal daily dosage can be administered in divided doses of two, three orfour times daily. Furthermore, any chimeric protein (and/or additionalagents) described herein can be administered continuously rather thanintermittently throughout the dosage regimen.

Cells and Nucleic Acids

In various embodiments, the present invention provides an expressionvector, comprising a nucleic acid encoding the chimeric proteindescribed herein. In various embodiments, the expression vectorcomprises DNA or RNA. In various embodiments, the expression vector is amammalian expression vector.

Both prokaryotic and eukaryotic vectors can be used for expression ofthe chimeric protein. Prokaryotic vectors include constructs based on E.coli sequences (see, e.g., Makrides, Microbiol Rev 1996, 60:512-538).Non-limiting examples of regulatory regions that can be used forexpression in E. coli include lac, trp, Ipp, phoA, recA, tac, T3, T7 andλP_(L). Non-limiting examples of prokaryotic expression vectors mayinclude the λgt vector series such as λgt11 (Huynh et al., in “DNACloning Techniques, Vol. I: A Practical Approach,” 1984, (D. Glover,ed.), pp. 49-78, IRL Press, Oxford), and the pET vector series (Studieret al., Methods Enzymol 1990, 185:60-89). Prokaryotic host-vectorsystems cannot perform much of the post-translational processing ofmammalian cells, however. Thus, eukaryotic host-vector systems may beparticularly useful. A variety of regulatory regions can be used forexpression of the chimeric proteins in mammalian host cells. Forexample, the SV40 early and late promoters, the cytomegalovirus (CMV)immediate early promoter, and the Rous sarcoma virus long terminalrepeat (RSV-LTR) promoter can be used. Inducible promoters that may beuseful in mammalian cells include, without limitation, promotersassociated with the metallothionein II gene, mouse mammary tumor virusglucocorticoid responsive long terminal repeats (MMTV-LTR), theβ-interferon gene, and the hsp70 gene (see, Williams et al., Cancer Res1989, 49:2735-42; and Taylor et al., Mol Cell Biol 1990, 10:165-75).Heat shock promoters or stress promoters also may be advantageous fordriving expression of the fusion proteins in recombinant host cells.

In some embodiments, expression vectors of the invention comprise anucleic acid encoding the chimeric proteins (and/or additional agents),or a complement thereof, operably linked to an expression controlregion, or complement thereof, that is functional in a mammalian cell.The expression control region is capable of driving expression of theoperably linked blocking and/or stimulating agent encoding nucleic acidsuch that the blocking and/or stimulating agent is produced in a humancell transformed with the expression vector.

Expression control regions are regulatory polynucleotides (sometimesreferred to herein as elements), such as promoters and enhancers, thatinfluence expression of an operably linked nucleic acid. An expressioncontrol region of an expression vector of the invention is capable ofexpressing operably linked encoding nucleic acid in a human cell. In anembodiment, the cell is a tumor cell. In another embodiment, the cell isa non-tumor cell. In an embodiment, the expression control regionconfers regulatable expression to an operably linked nucleic acid. Asignal (sometimes referred to as a stimulus) can increase or decreaseexpression of a nucleic acid operably linked to such an expressioncontrol region. Such expression control regions that increase expressionin response to a signal are often referred to as inducible. Suchexpression control regions that decrease expression in response to asignal are often referred to as repressible. Typically, the amount ofincrease or decrease conferred by such elements is proportional to theamount of signal present; the greater the amount of signal, the greaterthe increase or decrease in expression.

In an embodiment, the present invention contemplates the use ofinducible promoters capable of effecting high level of expressiontransiently in response to a cue. For example, when in the proximity ofa tumor cell, a cell transformed with an expression vector for thechimeric protein (and/or additional agents) comprising such anexpression control sequence is induced to transiently produce a highlevel of the agent by exposing the transformed cell to an appropriatecue. Illustrative inducible expression control regions include thosecomprising an inducible promoter that is stimulated with a cue such as asmall molecule chemical compound. Particular examples can be found, forexample, in U.S. Pat. Nos. 5,989,910, 5,935,934, 6,015,709, and6,004,941, each of which is incorporated herein by reference in itsentirety.

Expression control regions and locus control regions include full-lengthpromoter sequences, such as native promoter and enhancer elements, aswell as subsequences or polynucleotide variants which retain all or partof full-length or non-variant function. As used herein, the term“functional” and grammatical variants thereof, when used in reference toa nucleic acid sequence, subsequence or fragment, means that thesequence has one or more functions of native nucleic acid sequence(e.g., non-variant or unmodified sequence).

As used herein, “operable linkage” refers to a physical juxtaposition ofthe components so described as to permit them to function in theirintended manner. In the example of an expression control element inoperable linkage with a nucleic acid, the relationship is such that thecontrol element modulates expression of the nucleic acid. Typically, anexpression control region that modulates transcription is juxtaposednear the 5′ end of the transcribed nucleic acid (i.e., “upstream”).Expression control regions can also be located at the 3′ end of thetranscribed sequence (i.e., “downstream”) or within the transcript(e.g., in an intron). Expression control elements can be located at adistance away from the transcribed sequence (e.g., 100 to 500, 500 to1000, 2000 to 5000, or more nucleotides from the nucleic acid). Aspecific example of an expression control element is a promoter, whichis usually located 5′ of the transcribed sequence. Another example of anexpression control element is an enhancer, which can be located 5′ or 3′of the transcribed sequence, or within the transcribed sequence.

Expression systems functional in human cells are well known in the art,and include viral systems. Generally, a promoter functional in a humancell is any DNA sequence capable of binding mammalian RNA polymerase andinitiating the downstream (3′) transcription of a coding sequence intomRNA. A promoter will have a transcription initiating region, which isusually placed proximal to the 5′ end of the coding sequence, andtypically a TATA box located 25-30 base pairs upstream of thetranscription initiation site. The TATA box is thought to direct RNApolymerase II to begin RNA synthesis at the correct site. A promoterwill also typically contain an upstream promoter element (enhancerelement), typically located within 100 to 200 base pairs upstream of theTATA box. An upstream promoter element determines the rate at whichtranscription is initiated and can act in either orientation. Ofparticular use as promoters are the promoters from mammalian viralgenes, since the viral genes are often highly expressed and have a broadhost range. Examples include the SV40 early promoter, mouse mammarytumor virus LTR promoter, adenovirus major late promoter, herpes simplexvirus promoter, and the CMV promoter.

Typically, transcription termination and polyadenylation sequencesrecognized by mammalian cells are regulatory regions located 3′ to thetranslation stop codon and thus, together with the promoter elements,flank the coding sequence. The 3′ terminus of the mature mRNA is formedby site-specific post-translational cleavage and polyadenylation.Examples of transcription terminator and polyadenylation signals includethose derived from SV40. Introns may also be included in expressionconstructs.

There are a variety of techniques available for introducing nucleicacids into viable cells. Techniques suitable for the transfer of nucleicacid into mammalian cells in vitro include the use of liposomes,electroporation, microinjection, cell fusion, polymer-based systems,DEAE-dextran, viral transduction, the calcium phosphate precipitationmethod, etc. For in vivo gene transfer, a number of techniques andreagents may also be used, including liposomes; natural polymer-baseddelivery vehicles, such as chitosan and gelatin; viral vectors are alsosuitable for in vivo transduction. In some situations it is desirable toprovide a targeting agent, such as an antibody or ligand specific for atumor cell surface membrane protein. Where liposomes are employed,proteins which bind to a cell surface membrane protein associated withendocytosis may be used for targeting and/or to facilitate uptake, e.g.,capsid proteins or fragments thereof tropic for a particular cell type,antibodies for proteins which undergo internalization in cycling,proteins that target intracellular localization and enhanceintracellular half-life. The technique of receptor-mediated endocytosisis described, for example, by Wu et al., J. Biol. Chem. 262, 4429-4432(1987); and Wagner et al., Proc. Natl. Acad. Sci. USA 87, 3410-3414(1990).

Where appropriate, gene delivery agents such as, e.g., integrationsequences can also be employed. Numerous integration sequences are knownin the art (see, e.g., Nunes-Duby et al., Nucleic Acids Res. 26:391-406,1998; Sadwoski, J. Bacteriol., 165:341-357, 1986; Bestor, Cell,122(3):322-325, 2005; Plasterk et al., TIG 15:326-332, 1999; Kootstra etal., Ann. Rev. Pharm. Toxicol., 43:413-439, 2003). These includerecombinases and transposases. Examples include Cre (Sternberg andHamilton, J. Mol. Biol., 150:467-486, 1981), lambda (Nash, Nature, 247,543-545, 1974), Flp (Broach, et al., Cell, 29:227-234, 1982), R(Matsuzaki, et al., J. Bacteriology, 172:610-618, 1990), cpC31 (see,e.g., Groth et al., J. Mol. Biol. 335:667-678, 2004), sleeping beauty,transposases of the mariner family (Plasterk et al., supra), andcomponents for integrating viruses such as AAV, retroviruses, andantiviruses having components that provide for virus integration such asthe LTR sequences of retroviruses or lentivirus and the ITR sequences ofAAV (Kootstra et al., Ann. Rev. Pharm. Toxicol., 43:413-439, 2003). Inaddition, direct and targeted genetic integration strategies may be usedto insert nucleic acid sequences encoding the chimeric fusion proteinsincluding CRISPR/CAS9, zinc finger, TALEN, and meganuclease gene-editingtechnologies.

In one aspect, the invention provides expression vectors for theexpression of the chimeric proteins (and/or additional agents) that areviral vectors. Many viral vectors useful for gene therapy are known(see, e.g., Lundstrom, Trends Biotechnol., 21: 1 17, 122, 2003.Illustrative viral vectors include those selected from Antiviruses (LV),retroviruses (RV), adenoviruses (AV), adeno-associated viruses (AAV),and a viruses, though other viral vectors may also be used. For in vivouses, viral vectors that do not integrate into the host genome aresuitable for use, such as α viruses and adenoviruses. Illustrative typesof a viruses include Sindbis virus, Venezuelan equine encephalitis (VEE)virus, and Semliki Forest virus (SFV). For in vitro uses, viral vectorsthat integrate into the host genome are suitable, such as retroviruses,AAV, and Antiviruses. In one embodiment, the invention provides methodsof transducing a human cell in vivo, comprising contacting a solid tumorin vivo with a viral vector of the invention.

In various embodiments, the present invention provides a host cell,comprising the expression vector comprising the chimeric proteindescribed herein.

Expression vectors can be introduced into host cells for producing thepresent chimeric proteins. Cells may be cultured in vitro or geneticallyengineered, for example. Useful mammalian host cells include, withoutlimitation, cells derived from humans, monkeys, and rodents (see, forexample, Kriegler in “Gene Transfer and Expression: A LaboratoryManual,” 1990, New York, Freeman & Co.). These include monkey kidneycell lines transformed by SV40 (e.g., COS-7, ATCC CRL 1651); humanembryonic kidney lines (e.g., 293, 293-EBNA, or 293 cells subcloned forgrowth in suspension culture, Graham et al., J Gen Virol 1977, 36:59);baby hamster kidney cells (e.g., BHK, ATCC CCL 10); Chinese hamsterovary-cells-DHFR (e.g., CHO, Urlaub and Chasin, Proc Natl Acad Sci USA1980, 77:4216); DG44 CHO cells, CHO-K1 cells, mouse sertoli cells(Mather, Biol Reprod 1980, 23:243-251); mouse fibroblast cells (e.g.,NIH-3T3), monkey kidney cells (e.g., CV1 ATCC CCL 70); African greenmonkey kidney cells. (e.g., VERO-76, ATCC CRL-1587); human cervicalcarcinoma cells (e.g., HELA, ATCC CCL 2); canine kidney cells (e.g.,MDCK, ATCC CCL 34); buffalo rat liver cells (e.g., BRL 3A, ATCC CRL1442); human lung cells (e.g., W138, ATCC CCL 75); human liver cells(e.g., Hep G2, HB 8065); and mouse mammary tumor cells (e.g., MMT060562, ATCC CCL51). Illustrative cancer cell types for expressing thefusion proteins described herein include mouse fibroblast cell line,NIH3T3, mouse Lewis lung carcinoma cell line, LLC, mouse mastocytomacell line, P815, mouse lymphoma cell line, EL4 and its ovalbumintransfectant, E.G7, mouse melanoma cell line, B16F10, mouse fibrosarcomacell line, MC57, and human small cell lung carcinoma cell lines, SCLC #2and SCLC #7.

Host cells can be obtained from normal or affected subjects, includinghealthy humans, cancer patients, and patients with an infectiousdisease, private laboratory deposits, public culture collections such asthe American Type Culture Collection, or from commercial suppliers.

Cells that can be used for production of the present chimeric proteinsin vitro, ex vivo, and/or in vivo include, without limitation,epithelial cells, endothelial cells, keratinocytes, fibroblasts, musclecells, hepatocytes; blood cells such as T lymphocytes, B lymphocytes,monocytes, macrophages, neutrophils, eosinophils, megakaryocytes,granulocytes; various stem or progenitor cells, in particularhematopoietic stem or progenitor cells (e.g., as obtained from bonemarrow), umbilical cord blood, peripheral blood, fetal liver, etc. Thechoice of cell type depends on the type of tumor or infectious diseasebeing treated or prevented, and can be determined by one of skill in theart.

Subjects and/or Animals

In some embodiments, the subject and/or animal is a mammal, e.g., ahuman, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep,or non-human primate, such as a monkey, chimpanzee, or baboon. In otherembodiments, the subject and/or animal is a non-mammal, such, forexample, a zebrafish. In some embodiments, the subject and/or animal maycomprise fluorescently-tagged cells (with e.g. GFP). In someembodiments, the subject and/or animal is a transgenic animal comprisinga fluorescent cell.

In some embodiments, the subject and/or animal is a human. In someembodiments, the human is a pediatric human. In other embodiments, thehuman is an adult human. In other embodiments, the human is a geriatrichuman. In other embodiments, the human may be referred to as a patient.

In certain embodiments, the human has an age in a range of from about 0months to about 6 months old, from about 6 to about 12 months old, fromabout 6 to about 18 months old, from about 18 to about 36 months old,from about 1 to about 5 years old, from about 5 to about 10 years old,from about 10 to about 15 years old, from about 15 to about 20 yearsold, from about 20 to about 25 years old, from about 25 to about 30years old, from about 30 to about 35 years old, from about 35 to about40 years old, from about 40 to about 45 years old, from about 45 toabout 50 years old, from about 50 to about 55 years old, from about 55to about 60 years old, from about 60 to about 65 years old, from about65 to about 70 years old, from about 70 to about 75 years old, fromabout 75 to about 80 years old, from about 80 to about 85 years old,from about 85 to about 90 years old, from about 90 to about 95 years oldor from about 95 to about 100 years old.

In other embodiments, the subject is a non-human animal, and thereforethe invention pertains to veterinary use. In a specific embodiment, thenon-human animal is a household pet. In another specific embodiment, thenon-human animal is a livestock animal.

Kits

The invention provides kits that can simplify the administration of anyagent described herein. An illustrative kit of the invention comprisesany composition described herein in unit dosage form. In one embodiment,the unit dosage form is a container, such as a pre-filled syringe, whichcan be sterile, containing any agent described herein and apharmaceutically acceptable carrier, diluent, excipient, or vehicle. Thekit can further comprise a label or printed instructions instructing theuse of any agent described herein. The kit may also include a lidspeculum, topical anesthetic, and a cleaning agent for theadministration location. The kit can also further comprise one or moreadditional agent described herein. In one embodiment, the kit comprisesa container containing an effective amount of a composition of theinvention and an effective amount of another composition, such thosedescribed herein. The invention will be further described in thefollowing example, which does not limit the scope of the inventiondescribed in the claims.

EXAMPLES Example 1. Construction and Characterization of MousePD-1-Fc-OX40L Construct

A chimeric mouse PD-1-Fc-OX40L construct was generated and itsexpression in CHO-K1 cells was verified using a mouse IgG capture ELISAassay (here, the Fc is derived from IgG1). Specifically, CHO-K1 cellswere stably nucleofected with pVITRO2-GS-hygro or pcDNA3.4 vectorsexpressing either the mouse extracellular domain (ECD) of PD-1 fused toFc (mPD-1-Fc) or mPD-1-Fc fused to the ECD of OX40L (mPD-1-Fc-OX40L).Antibiotic-resistant single cell clones were isolated via limitingdilution. The concentration of each chimeric protein secreted into theculture media was determined by a mIgG capture ELISA as shown in FIG. 5.

Binding assays were carried out to characterize the ability of mousePD-1-Fc-OX40L to bind to mOX40 as well as to mPD-L1. FIG. 6A shows aschematic representation of the ELISA assay used to detect binding ofmouse PD-1-Fc-OX40L to mOX40. Specifically, recombinant mOX40 fused tohuman Fc (mOX40-hFc) was used to capture mPD-1-Fc-OX40L in the culturemedia. A rabbit polyclonal antibody to mPD-1 was used to detect themPD-1 domain in the chimeric protein and subsequently detected using ahorseradish peroxidase (HRP)-conjugated polyclonal antibody to rabbitIgG (H+L). FIG. 6B shows that mouse PD-1-Fc-OX40L efficiently bound toOX40 compared to the mPD-1-Fc negative control. FIG. 7A shows aschematic representation of the ELISA assay used to detect binding ofmouse PD-1-Fc-OX40L to mPD-L1.

Specifically, recombinant mPD-L1 fused to human Fc (mPD-L1-hFc) was usedto capture the mPD-1-Fc-OX40L chimeric protein in the culture media. Ahorseradish peroxidase (HRP)-conjugated polyclonal antibody to mouse IgG(H+L) was used for the detection of the bound proteins. FIG. 7B showsthat mouse PD-1-Fc-OX40L efficiently bound to PD-L1 as compared to anegative media control and a positive control using recombinant mousePD1-Fc.

Experiments were carried out to characterize the activity of mousePD-1-Fc-OX40L in eliciting T-cell response and in treating tumors.Chicken ovalbumin antigen-specific OT-I/EGFP, CD8+ T cells (5×10⁵) wereadoptively transferred to C57/BL6-albino mice via tail vein injections 2days prior to inoculation with B16.F10-ova tumor cells (5×10⁵) into theright flank of the mice. Once tumors reached 3-5 mm in diameter,PD-1-Fc-OX40L expressing DNA (50 μg) was electroporated into the tumorusing a defined electrical pulse (1500 V/cm) using 8 pulses at 100 ρS.The percentage of CD8+OT-I/EGFP cells in the peripheral blood wasquantified by flow cytometry analysis over the assigned time coursefollowing electroporation. As shown in FIG. 8, in vivo intratumoraldelivery of mouse (m) PD-1-Fc-OX40L led to an expansion ofantigen-specific CD8+ T-cells.

FIG. 9 shows that the in vivo intratumoral delivery of mPD-1-Fc-OX40Lalso led to tumor regression in the B16.F10-ova tumor model. B16.F10-ovatumors were generated in C57/B16-albino mice that were adoptivelytransferred with CD8+OT-I/EGFP cells and electroporated once withmPD-1-Fc-OX40L expressing DNA (50 μg). Control mice did not receive DNAbut were subjected to electroporation (EP only). Tumor diameters weremeasured using a digital caliper over the assigned time course followingelectroporation. FIG. 9 demonstrates that the administration ofmPD-1-Fc-OX40L significantly reduced tumor size.

Example 2. Additional Characterization of Mouse PD-1-Fc-OX40L Construct

A mPD-1-Fc-OX40L construct was generated which included the mouseextracellular domain (ECD) of PD-1 fused to the ECD of OX40L via ahinge-CH2-CH3 Fc domain derived from IgG1 (mPD-1-Fc-OX40L). ThemPD-1-Fc-OX40L construct was transiently expressed in 293 cells andpurified using protein A affinity chromatography. Western blot andfunctional ELISA analysis were performed to validate the detection andbinding of all 3 components of mPD-1-Fc-OX40L (FIG. 10A). Quanitation ofmPD1-Fc-OX40L can be assessed using a murine IgG capture and detectionELISA (FIG. 10B). The binding of mPD-1 and mOX40L to their partnersmPD-L1 and mOX40, respectively, was demonstrated simultaneously bycapturing mPD-1-Fc-OX40L with mPD-L1-Fc and detecting it with mOX40-His,followed by His-HRP for chemiluminescence quantitation (FIG. 8C). It wasalso noted that there were monomeric and dimeric conformations ofmPD-1-Fc-OX40L.

To assess the ex vivo cellular binding of mPD-1-Fc-OX40L, primary mousesplenocytes were isolated and activated for 2 days withPMA/PHA/llonomycin, in order to up-regulate OX40 and PD-L1 expression.Activated splenocytes were then treated with 500 ng/mL of mPD-1-Fc-OX40Land analyzed by flow cytometry for binding (Fc-PE) (FIG. 8D). To isolatePD-L1 expressing cells, splenocytes were co-stained with an antibodytargeting MHC II on antigen presenting cells (I-A/I-E). To isolate OX40expressing cells, splenocytes were co-stained with CD4. mPD-1-Fc-OX40Lbound significantly to both PD-L1+ and OX40+ populations of splenocytes,indicating that mPD-1-Fc-OX40L had been generated and purifiedcompetently to bind its targets on primary derived cells. The bindingactivity of mPD1-Fc-OX40L to primary mouse tumor cell lines expressingPD-L1 was also assessed. The murine 4T1 tumor cell line was identifiedas expressing low amounts of PD-L1 and the B16.F10 tumor cell lineexpressed comparatively high amounts of PD-L1. mPD1-Fc-OX40L was shownto bind the PD-L1 positive B16.F10 tumor cell line to a greater extentthan the PD-L1 low 4T1 tumor cell line (FIG. 10E).

Additional functional activities of mPD-1-Fc-OX40L were characterizedusing a T cell activation/tumor co-culture assay. First, murinePD-L11_(low) (4T1) and PD-Li_(high) (B16.F10) cells were identified byflow cytometry (FIG. 8E). Next, mouse splenocytes were activated for 2days with CD3/CD28 beads and a sub-saturating concentration of IL2.After 2 days, activated splenocytes were co-cultured with eitherirradiated 4T1 or B16.F10 cells in the presence or absence ofmPD-1-Fc-OX40L. Five days after the initial isolation of splenocytes,culture medium was collected and analyzed for the cytokine IL2 by ELISA(FIG. 8F). It was observed that mPD-1-Fc-OX40L was capable ofsignificant induction of IL2 secretion, especially in co-culturescontaining PD-Li_(high) tumor cells. Without wishing to be bound bytheory, it is believed that mPD-1-Fc-OX40L was concomitantly blockingthe suppressive effects of PD-L1 while also activating T cells viaOX40/OX40L signaling, thereby inducing IL2 secretion. Altogether, thesefindings suggest that mPD-1-Fc-OX40L may provide significant anti-tumorimmunity in pre-clinical models.

The anti-tumor potency of mPD-1-Fc-OX40L was tested using severalpreclinical tumor model systems. Specifically murine models ofcolorectal cancer (CT26 and MC38) were used to assess the effects ofmPD-1-Fc-OX40L on tumor growth, overall survival, and the induction of aserum cytokine response following therapy. These experiments wereperformed head-to-head with extensively characterized OX40 agonist(OX86) and PD-L1 blocking (10F.9G2) antibodies given as monotherapy orin combination, at an equivalent active dose to mPD-1-Fc-OX40L viaintraperitoneal injection (2 doses of 100 ug each). As shown in FIG.11A, mPD-1-Fc-OX40L significantly reduced tumor size in the MC38 model.More particularly, administration of mPD-1-Fc-OX40L resulted in greatertumor regression than the OX40 agonist and PD-L1 blocking antibodiesadministered individually or in combination. Importantly, repeatchallenge of mice that rejected the primary tumor with the parental MC38tumor cell line was performed for each group. These data demonstratedthat, in the absence of repeat treatment, mice treated withmPD1-Fc-OX40L were able to reject a re-challenge with the parental tumorto a greater degree than any of the other treatment groups (FIG. 11A andFIG. 11B). Further, other fusion constructs including mPD1-Fc-GITRL andmPD1-Fc-41BBL were produced and used in tumor bearing mice as describedabove for mPD1-Fc-OX40L. Both the GITRL and 41BBL containing constructsled to reduced tumor size in treated animals.

In addition to measuring tumor size, a pharmacodynamic biomarker formPD-1-Fc-OX40L signaling in vivo was also determined. Specifically, aserum cytokine analysis for mice treated with anti-PD-L1 and anti-OX40antibodies as well as with PD-1-Fc-OX40L was performed. As shown in FIG.11B and FIG. 11C, there was a dose-dependent cytokine signaturefollowing treatment with mPD-1-Fc-OX40L that was remarkably similar tothe cytokine signature observed following combined administration ofanti-PD-L1 and anti-OX40 antibodies, comprising of increased IFNγ, TNFα,IL-2, IL-4, IL-5, IL-6, IL-10, IL-17A and IL-22 (FIG. 11C, FIG. 11D, andFIG. 11J). Importantly, detection of a serum cytokine response followingtreatment with mPD1-Fc-OX40L was shown to be dose dependent.Specifically, treatment with one or two injections of 40 μg did not leadto a detectable serum cytokine response, while treatment with 100 μgonce led to an intermediate cytokine response and treatment with 100 μgtwo times led to a higher cytokine response (FIG. 11K). Treatment ofmice with mPD1-Fc-GITRL was also shown to stimulated a specific serumcytokine response.

In some experiments, mice bearing MC38 tumors were sacrificed on day 13of the experiment to evaluate the cellular immune response in the tumor,peripheral blood and spleen. On day 13 of the experiment, mPD1-Fc-OX40L,mPD1-Fc-GITRL and mCD172a-Fc-CD40L were all shown to cause reduced tumorgrowth as compared to untreated animals or animals treated with OX40agonist antibodies, GITR agonist antibodies or PD-L1 blocking antibodies(FIG. 11E). In accordance with these data, mice treated withmPD1-Fc-OX40L or mPD1-Fc-GITRL were shown to have increased numbers oftumor antigen specific tumor infiltrating lymphocytes (TIL) on day 13 ofthe experiment (FIG. 11F). Analysis of the memory phenotype in thespleen of CD8+ T cells was performed (FIG. 11G) and the CD4/CD8 T cellratio was also compared across multiple treatments (FIG. 11H).

The pharmacodynamic biomarkers for PD-1-Fc-OX40L signaling in vivo wasalso determined using the CT26 model. Specifically, a serum cytokineanalysis for mice treated with anti-PD-L1 and anti-OX40 antibodies,individually or in combination, as well as with PD-1-Fc-OX40L wasperformed. As shown in FIG. 11D, the cytokine signature followingtreatment with mPD-1-Fc-OX40L was remarkably similar to the cytokinesignature observed following the combined administration of anti-PD-L1and anti-OX40 antibodies. Specifically, the cytokine signature comprisedof increased IFNγ, TNFα, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13,IL-17A, IL-17F, and IL-22 (FIG. 11J and FIG. 11K).

Consistent with the results derived from the MC38 model, administrationof mPD-1-Fc-OX40L also significantly reduced tumor size in the CT26colorectal cancer model. Particularly, use of mPD-1-Fc-OX40L resulted ingreater tumor regression than the OX40 agonist and PD-L1 blockingantibodies (FIG. 11L). Further, mice administered with mPD-1-Fc-OX40Lexhibited longer survival time than mice administered with the OX40agonist and PD-L1 blocking antibodies (FIG. 11L). In addition, otherchimeric fusion protein constructs including PD1-Fc-GITRL, PD1-Fc-41BBLand PD1-Fc-TL1A were all shown to exhibit delayed tumor growth anregression in the CT26 model (FIG. 11L).

Altogether, these data clearly demonstrate, inter alia, the functionalactivity of mPD-1-Fc-OX40L in vivo.

Example 3. Construction and Characterization of Human PD-1-Fc-OX40L

A human PD-1-Fc-OX40L comprising human PD-1 linked to OX40L via ahinge-CH2-CH3 Fc domain derived from the human immunoglobulin 4 (IgG4)antibody was constructed. This construct was referred to as SL-279252.

The mRNA sequence of human OX40L was as follows (bold text— CDS ofOX40L; bold & underlined text—extracellular domain of OX40L):

(SEQ ID NO: 16) 1TCAATCGCCTTTTATCTCTGGCCCTGGGACCTTTGCCTATTTTCTGATTGATAGGCTTTG 61TTTTGTCTTTACCTCCTTCTTTCTGGGGAAAACTTCAGTTTTATCGCACGTTCCCCTTTT 121CCATATCTTCATCTTCCCTCTACCCAGATTGTGAAGATGGAAAGGGTCCAACCCCTGGAA 181GAGAATGTGGGAAATGCAGCCAGGCCAAGATTCGAGAGGAACAAGCTATTGCTGGTGGCC 241TCTGTAATTCAGGGACTGGGGCTGCTCCTGTGCTTCACCTACATCTGCCTGCACTTCTCT 301 GCTCTTCAGGTATCACATCGGTATCCTCGAATTCAAAGTATCAAAGTACAATTTACCGAA 361TATAAGAAGGAGAAAGGTTTCATCCTCACTTCCCAAAAGGAGGATGAAATCATGAAGGTG 421CAGAACAACTCAGTCATCATCAACTGTGATGGGTTTTATCTCATCTCCCTGAAGGGCTAC 481TTCTCCCAGGAAGTCAACATTAGCCTTCATTACCAGAAGGATGAGGAGCCCCTCTTCCAA 541CTGAAGAAGGTCAGGTCTGTCAACTCCTTGATGGTGGCCTCTCTGACTTACAAAGACAAA 601GTCTACTTGAATGTGACCACTGACAATACCTCCCTGGATGACTTCCATGTGAATGGCGGA 661GAACTGATTCTTATCCATCAAAATCCTGGTGAATTCTGTGTCCTTTGA GGGGCTGATGGC 721AATATCTAAAACCAGGCACCAGCATGAACACCAAGCTGGGGGTGGACAGGGCATGGATTC 781TTCATTGCAAGTGAAGGAGCCTCCCAGCTCAGCCACGTGGGATGTGACAAGAAGCAGATC 841CTGGCCCTCCCGCCCCCACCCCTCAGGGATATTTAAAACTTATTTTATATACCAGTTAAT 901CTTATTTATCCTTATATTTTCTAAATTGCCTAGCCGTCACACCCCAAGATTGCCTTGAGC 961CTACTAGGCACCTTTGTGAGAAAGAAAAAATAGATGCCTCTTCTTCAAGATGCATTGTTT 1021CTATTGGTCAGGCAATTGTCATAATAAACTTATGTCATTGAAAACGGTACCTGACTACCA 1081TTTGCTGGAAATTTGACATGTGTGTGGCATTATCAAAATGAAGAGGAGCAAGGAGTGAAG 1141GAGTGGGGTTATGAATCTGCCAAAGGTGGTATGAACCAACCCCTGGAAGCCAAAGCGGCC 1201TCTCCAAGGTTAAATTGATTGCAGTTTGCATATTGCCTAAATTTAAACTTTCTCATTTGG 1261TGGGGGTTCAAAAGAAGAATCAGCTTGTGAAAAATCAGGACTTGAAGAGAGCCGTCTAAG 1321AAATACCACGTGCTTTTTTTCTTTACCATTTTGCTTTCCCAGCCTCCAAACATAGTTAAT 1381AGAAATTTCCCTTCAAAGAACTGTCTGGGGATGTGATGCTTTGAAAAATCTAATCAGTGA 1441CTTAAGAGAGATTTTCTTGTATACAGGGAGAGTGAGATAACTTATTGTGAAGGGTTAGCT 1501TTACTGTACAGGATAGCAGGGAACTGGACATCTCAGGGTAAAAGTCAGTACGGATTTTAA 1561TAGCCTGGGGAGGAAAACACATTCTTTGCCACAGACAGGCAAAGCAACACATGCTCATCC 1621TCCTGCCTATGCTGAGATACGCACTCAGCTCCATGTCTTGTACACACAGAAACATTGCTG 1681GTTTCAAGAAATGAGGTGATCCTATTATCAAATTCAATCTGATGTCAAATAGCACTAAGA 1741AGTTATTGTGCCTTATGAAAAATAATGATCTCTGTCTAGAAATACCATAGACCATATATA 1801GTCTCACATTGATAATTGAAACTAGAAGGGTCTATAATCAGCCTATGCCAGGGCTTCAAT 1861GGAATAGTATCCCCTTATGTTTAGTTGAAATGTCCCCTTAACTTGATATAATGTGTTATG 1921CTTATGGCGCTGTGGACAATCTGATTTTTCATGTCAACTTTCCAGATGATTTGTAACTTC 1981TCTGTGCCAAACCTTTTATAAACATAAATTTTTGAGATATGTATTTTAAAATTGTAGCAC 2041ATGTTTCCCTGACATTTTCAATAGAGGATACAACATCACAGAATCTTTCTGGATGATTCT 2101GTGTTATCAAGGAATTGTACTGTGCTACAATTATCTCTAGAATCTCCAGAAAGGTGGAGG 2161GCTGTTCGCCCTTACACTAAATGGTCTCAGTTGGATTTTTTTTTCCTGTTTTCTATTTCC 2221TCTTAAGTACACCTTCAACTATATTCCCATCCCTCTATTTTAATCTGTTATGAAGGAAGG 2281TAAATAAAAATGCTAAATAGAAGAAATTGTAGGTAAGGTAAGAGGAATCAAGTTCTGAGT 2341GGCTGCCAAGGCACTCACAGAATCATAATCATGGCTAAATATTTATGGAGGGCCTACTGT 2401GGACCAGGCACTGGGCTAAATACTTACATTTACAAGAATCATTCTGAGACAGATATTCAA 2461TGATATCTGGCTTCACTACTCAGAAGATTGTGTGTGTGTTTGTGTGTGTGTGTGTGTGTG 2521TATTTCACTTTTTGTTATTGACCATGTTCTGCAAAATTGCAGTTACTCAGTGAGTGATAT 2581CCGAAAAAGTAAACGTTTATGACTATAGGTAATATTTAAGAAAATGCATGGTTCATTTTT 2641AAGTTTGGAATTTTTATCTATATTTCTCACAGATGTGCAGTGCACATGCAGGCCTAAGTA 2701TATGTTGTGTGTGTTGTTTGTCTTTGATGTCATGGTCCCCTCTCTTAGGTGCTCACTCGC 2761TTTGGGTGCACCTGGCCTGCTCTTCCCATGTTGGCCTCTGCAACCACACAGGGATATTTC 2821TGCTATGCACCAGCCTCACTCCACCTTCCTTCCATCAAAAATATGTGTGTGTGTCTCAGT 2881CCCTGTAAGTCATGTCCTTCACAGGGAGAATTAACCCTTCGATATACATGGCAGAGTTTT 2941GTGGGAAAAGAATTGAATGAAAAGTCAGGAGATCAGAATTTTAAATTTGACTTAGCCACT 3001AACTAGCCATGTAACCTTGGGAAAGTCATTTCCCATTTCTGGGTCTTGCTTTTCTTTCTG 3061TTAAATGAGAGGAATGTTAAATATCTAACAGTTTAGAATCTTATGCTTACAGTGTTATCT 3121GTGAATGCACATATTAAATGTCTATGTTCTTGTTGCTATGAGTCAAGGAGTGTAACCTTC 3181TCCTTTACTATGTTGAATGTATTTTTTTCTGGACAAGCTTACATCTTCCTCAGCCATCTT 3241TGTGAGTCCTTCAAGAGCAGTTATCAATTGTTAGTTAGATATTTTCTATTTAGAGAATGC 3301TTAAGGGATTCCAATCCCGATCCAAATCATAATTTGTTCTTAAGTATACTGGGCAGGTCC 3361CCTATTTTAAGTCATAATTTTGTATTTAGTGCTTTCCTGGCTCTCAGAGAGTATTAATAT 3421TGATATTAATAATATAGTTAATAGTAATATTGCTATTTACATGGAAACAAATAAAAGATC 3481TCAGAATTCACTA

The amino acid sequence of human OX40L was as follows(bolded—extracellular domain):

(SEQ ID NO: 17) MERVQPLEENVGNAARPRFERNKLLLVASVIQGLGLLLCFTYICLHFSALQVSHRYPRIQSIKVQFTEYKKEKGFILTSQKEDEIMKVQNNSVIINCDGFYLISLKGYFSQEVNISLHYQKDEEPLFQLKKVRSVNSLMVASLTYKDKVYLNVTTDNTSLDDFHVNGGELILIHQNPGEFCVL

The nucleic acid sequence of the hinge-CH2-CH3 Sequence from human IgG4was as follows:

(SEQ ID NO: 18) TCTAAGTACGGCCCTCCCTGCCCTAGCTGTCCCGCCCCTGAATTTCTGGGCGGACCCTCCGTGTTTCTGTTCCCCCCAAAGCCCAAGGACACCCTGATGATCAGCCGGACCCCCGAAGTGACCTGTGTGGTGGTGGATGTGTCCCAGGAAGATCCCGAGGTGCAGTTCAATTGGTACGTGGACGGGGTGGAAGTGCACAACGCCAAGACCAAGCCCAGAGAGGAACAGTTCAACAGCACCTACCGGGTGGTGTCTGTGCTGACCGTGCTGCACCAGGATTGGCTGAGCGGCAAAGAGTACAAGTGCAAGGTGTCCAGCAAGGGCCTGCCCAGCAGCATCGAAAAGACCATCAGCAACGCCACCGGCCAGCCCAGGGAACCCCAGGTGTACACACTGCCCCCTAGCCAGGAAGAGATGACCAAGAACCAGGTGTCCCTGACATGCCTCGTGAAGGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGAGCAACGGCCAGCCAGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCTCATTCTTCCTGTACTCCCGGCTGACAGTGGACAAGAGCAGCTGGCAGGAAGGCAACGTGTTCAGCTGCAGCGTGATGCACGAAGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGTCCCTGGGCAAA

The cDNA sequence of human PD-1 was as follows:

(SEQ ID NO: 19) ATGCAGATCCCACAGGCGCCCTGGCCAGTCGTCTGGGCGGTGCTACAACTGGGCTGGCGGCCAGGATGGTTCTTAGACTCCCCAGACAGGCCCTGGAACCCCCCCACCTTCTCCCCAGCCCTGCTCGTGGTGACCGAAGGGGACAACGCCACCTTCACCTGCAGCTTCTCCAACACATCGGAGAGCTTCGTGCTAAACTGGTACCGCATGAGCCCCAGCAACCAGACGGACAAGCTGGCCGCCTTCCCCGAGGACCGCAGCCAGCCCGGCCAGGACTGCCGCTTCCGTGTCACACAACTGCCCAACGGGCGTGACTTCCACATGAGCGTGGTCAGGGCCCGGCGCAATGACAGCGGCACCTACCTCTGTGGGGCCATCTCCCTGGCCCCCAAGGCGCAGATCAAAGAGAGCCTGCGGGCAGAGCTCAGGGTGACAGAGAGAAGGGCAGAAGTGCCCACAGCCCACCCCAGCCCCTCACCCAGGCCAGCCGGCCAGTTCCAAACCCTGGTGGTTGGTGTCGTGGGCGGCCTGCTGGGCAGCCTGGTGCTGCTAGTCTGGGTCCTGGCCGTCATCTGCTCCCGGGCCGCACGAGGGACAATAGGAGCCAGGCGCACCGGCCAGCCCCTGAAGGAGGACCCCTCAGCCGTGCCTGTGTTCTCTGTGGACTATGGGGAGCTGGATTTCCAGTGGCGAGAGAAGACCCCGGAGCCCCCCGTGCCCTGTGTCCCTGAGCAGACGGAGTATGCCACCATTGTCTTTCCTAGCGGAATGGGCACCTCATCCCCCGCCCGCAGGGGCTCAGCTGACGGCCCTCGGAGTGCCCAGCCACTGAGGCCTGAGGATGGACACTGCTCTTGGCCCCTCTGA

The nucleic acid sequence of human PD-1-Fc-OX40L was as follows:

(SEQ ID NO: 20) GTCGACGCCACCATGCAGATCCCACAGGCGCCCTGGCCAGTCGTCTGGGCGGTGCTACAACTGGGCTGGCGGCCAGGATGGTTCTTAGACTCCCCAGACAGGCCCTGGAACCCCCCCACCTTCTCCCCAGCCCTGCTCGTGGTGACCGAAGGGGACAACGCCACCTTCACCTGCAGCTTCTCCAACACATCGGAGAGCTTCGTGCTAAACTGGTACCGCATGAGCCCCAGCAACCAGACGGACAAGCTGGCCGCCTTCCCCGAGGACCGCAGCCAGCCCGGCCAGGACTGCCGCTTCCGTGTCACACAACTGCCCAACGGGCGTGACTTCCACATGAGCGTGGTCAGGGCCCGGCGCAATGACAGCGGCACCTACCTCTGTGGGGCCATCTCCCTGGCCCCCAAGGCGCAGATCAAAGAGAGCCTGCGGGCAGAGCTCAGGGTGACAGAGAGAAGGGCAGAAGTGCCCACAGCCCACCCCAGCCCCTCACCCAGGCCAGCCGGCCAGTTCCAATCTAAGTACGGCCCTCCCTGCCCTAGCTGTCCCGCCCCTGAATTTCTGGGCGGACCCTCCGTGTTTCTGTTCCCCCCAAAGCCCAAGGACACCCTGATGATCAGCCGGACCCCCGAAGTGACCTGTGTGGTGGTGGATGTGTCCCAGGAAGATCCCGAGGTGCAGTTCAATTGGTACGTGGACGGGGTGGAAGTGCACAACGCCAAGACCAAGCCCAGAGAGGAACAGTTCAACAGCACCTACCGGGTGGTGTCTGTGCTGACCGTGCTGCACCAGGATTGGCTGAGCGGCAAAGAGTACAAGTGCAAGGTGTCCAGCAAGGGCCTGCCCAGCAGCATCGAAAAGACCATCAGCAACGCCACCGGCCAGCCCAGGGAACCCCAGGTGTACACACTGCCCCCTAGCCAGGAAGAGATGACCAAGAACCAGGTGTCCCTGACATGCCTCGTGAAGGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGAGCAACGGCCAGCCAGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCTCATTCTTCCTGTACTCCCGGCTGACAGTGGACAAGAGCAGCTGGCAGGAAGGCAACGTGTTCAGCTGCAGCGTGATGCACGAAGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGTCCCTGGGCAAAATAGAGGGACGAATGGACcaggtatcacatcggtatcctcgaattcaaagtatcaaagtacaatttaccgaatataagaaggagaaaggtttcatcctcacttcccaaaaggaggatgaaatcatgaaggtgcagaacaactcagtcatcatcaactgtgatgggttttatctcatctccctgaagggctacttctcccaggaagtcaacattagccttcattaccagaaggatgaggagcccctcttccaactgaagaaggtcaggtctgtcaactccttgatggtggcctctctgacttacaaagacaaagtctacttgaatgtgaccactgacaatacctccctggatgacttccatgtgaatggcggagaactgattcttatccatcaaaatcctggtgaattctgtgtccttTGAGTCGAC

The sequence was codon optimized for expression by Chinese Hamster (CHO)cells as follows:

(SEQ ID NO: 21) CACCGGCGAGATCTGCCACCATGCAGATCCCTCAGGCCCCCTGGCCTGTCGTGTGGGCTGTGCTGCAGCTGGGATGGCGGCCTGGCTGGTTCCTGGACTCTCCTGACAGACCCTGGAACCCCCCCACCTTTAGCCCTGCTCTGCTGGTCGTGACCGAGGGCGACAACGCCACCTTCACCTGTTCCTTCAGCAACACCTCCGAGTCCTTCGTGCTGAACTGGTACAGAATGTCCCCCAGCAACCAGACCGACAAGCTGGCCGCCTTCCCCGAGGATAGATCCCAGCCTGGACAGGACTGCCGGTTCAGAGTGACCCAGCTGCCCAACGGCCGGGACTTCCACATGTCTGTCGTGCGGGCCAGACGGAACGACTCCGGCACATATCTGTGCGGCGCCATCTCCCTGGCCCCCAAGGCTCAGATCAAAGAGTCTCTGCGGGCCGAGCTGAGAGTGACCGAGAGAAGGGCTGAGGTGCCAACCGCCCACCCTAGCCCATCTCCAAGACCTGCCGGCCAGTTCCAGTCTAAGTACGGCCCTCCTTGCCCTAGCTGCCCTGCCCCTGAATTTCTGGGCGGACCCTCCGTGTTCCTGTTCCCCCCAAAGCCCAAGGACACCCTGATGATCTCCCGGACCCCCGAAGTGACCTGCGTGGTGGTGGATGTGTCCCAGGAAGATCCCGAGGTGCAGTTCAATTGGTACGTGGACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCCAGAGAGGAACAGTTCAACTCCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGTCCGGCAAAGAGTACAAGTGCAAGGTGTCCTCCAAGGGCCTGCCCTCCAGCATCGAAAAGACCATCTCTAACGCCACCGGCCAGCCCCGGGAACCCCAGGTGTACACACTGCCTCCAAGCCAGGAAGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTCGTGAAGGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCTGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACTCCGACGGCTCCTTCTTCCTGTACTCCCGCCTGACCGTGGACAAGTCCTCCTGGCAGGAAGGCAACGTGTTCTCCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGTCCCTGTCTCTGGGCAAGATCGAGGGCCGGATGGATCAGGTGTCACACAGATACCCCCGGATCCAGTCCATCAAAGTGCAGTTTACCGAGTACAAGAAAGAGAAGGGATTCATCCTGACCTCCCAGAAAGAGGACGAGATCATGAAGGTGCAGAACAACTCCGTGATCATCAACTGCGACGGGTTCTACCTGATCTCCCTGAAGGGCTACTTCAGTCAGGAAGTGAACATCAGCCTGCACTACCAGAAGGACGAGGAACCCCTGTTCCAGCTGAAGAAAGTGCGGAGCGTGAACTCCCTGATGGTGGCCTCTCTGACCTACAAGGACAAGGTGTACCTGAACGTGACCACCGACAATACCTCCCTGGACGACTTCCACGTGAACGGCGGCGAGCTGATCCTGATCCACCAGAACCCTGGCGAGTTCTGCGTGCTGTGACTCGAGG CTAGC

Accordingly, the amino acid sequence of SL-279252 was as follows:

(SEQ ID NO: 22) MQIPQAPWPWWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVNTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVNRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQSKYGPPCPSCPAPEFLGGPSVFLFPPKPKDILMISRTPEVICWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNATGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSSWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKIEGRMDQVSHRYPRIQSIKVQFTEYKKEKGFILTSQKEDEIMKVQNNSVIINCDGFYLISLKGYFSQEVNISLHYQKDEEPLFQLKKVRSVNSLMVASLTYKDKVYLNVTTDNTSLDDFHVNGGELILIHQNPGEFCVL

Alternatively, SL-279252 may include other signaling peptides such asthose derived from human collagen V or human IgG heavy chain.Alternatively, SL-279252 may include one or more mutations in the Fcdomain to increase stability or to increase binding affinity to FcRn,such as those previously described. The human PD-1-Fc-OX40L constructwas imported into the protein tertiary prediction software RaptorX, toensure proper folding of the three major domains (see FIG. 12A). Thetertiary structures of each component (i.e., PD-1, Fc, and OX40L)adopted their native conformations within the larger macromolecule,suggesting that PD-1-Fc-OX40L would retain binding capability andmolecular function of all domains. Next, the immunogenic probability ofPD-1-Fc-OX40L was assessed using an in si/lico molecular modelingalgorithm, cross-referenced to a T cell epitope database(ABZENA/ANTITOPE, FIG. 12B). Although all coding sequences were human,there was minimal potential for lead and linker sequences to elicit animmune response following treatment. Further analysis was performedusing the iTope antigen prediction technology in silico (ANTITOPE).Based on this analysis, SL-279252 was predicted to have a ‘low-risk’ ofimmunogenicity because no identifiable T cell epitopes were detected.Accordingly, SL-279252 was expected to have low immunogenicity. Thecodon-optimized DNA sequence of SL-279252 was then synthesized anddirectionally cloned into pcDNA3.4-hygro-mcs (THERMO FISHER) andpVITRO2-hygro-mcs (INVIVOGEN) expression vectors.

Vectors were then either transiently or stably transfected into CHO-K1and 293T cells, and culture supernatants were purified using standardprotein A agarose affinity chromatography. Human Fc/IgG ELISAs on elutedfractions (from stable transfection experiments) of purified proteinshow definitive peaks that align with the first major peak detected froma large-scale purification obtained from transient transfectionexperiments (FIG. 13A), indicating that successful production ofSL-279252 can be achieved using routine protein purification techniquessuch as protein A.

To confirm that all three domains of SL-279252 are intact andrecognizable by a protein detection assay, Western blot analysis wasperformed on purified fusion protein probing for human anti-PD-1,anti-Fc, and anti-OX40L (FIG. 13B). SL-279252 was detected by all threeantibodies and when the protein was run under reducing conditions,migrated at approximately 75 kDa. Approximately 50% of the non-reducedprotein ran as a dimer, which was a potential advantage, given the invivo oligomerization associated with OX40/L signaling and function. Thepredicted molecular weight for SL-279252 was 60.3 kDa. The reducedfraction of SL-279252 was detected at a higher molecular weight, which,without wishing to be bound by theory, may be due to glycosylation. Thiswas verified by treating SL-279252 with a protein deglycosylase, PNGaseF (FIG. 13B). Following deglycosylation, the reduced fraction ofSL-279252 migrated exactly at the predicted molecular weight of 60.3kDa. This provided evidence that SL-279252 was co/post-translationallymodified through glycosylation, which played essential roles in theproper folding and stability of proteins, and cell-to-cell adhesion(Dalziel M, Dwek R A. Science 2014, Maverakis E, Lebrilla C B. JAutoimmun. 2015).

Next, analysis was performed to determine whether SL-279252 was able tobind to its receptor/ligand targets using plate-immobilized recombinantproteins in functional ELISA assays. SL-279252 was successfully capturedwith recombinant human OX40 (FIG. 13C), and detected with anti-humanOX40L/anti-goat HRP. In this regard, the capture of SL-279252 with humanOX40, followed by detection with a two-step incubation withgoat-anti-OX40L followed by anti-goat-HRP led to efficient detection. Toestablish whether both ends of SL-279252 could bind their respectivereceptor/ligand simultaneously, another ELISA assay was developed whichcaptures SL-279252 using plate absorbed human PD-L1 and detectsSL-279252 using recombinant OX40-his (FIG. 13D). This assay demonstratesthat SL-279252 can simultaneously bind human PD-L1 and human OX40.

Next, surface plasmon resonance (SPR) analysis was performed todetermine the affinity by which SL-279252 bound to hPD-L1, hPD-L1, hOX40and various human Fc receptors (FIG. 14A to FIG. 14O). Specifically,polyhistidine-tagged versions of recombinant human PD-L1, PD-L2 andhuman OX40 was bound to ProteOn HTG tris-NTA chips (BIORAD). SL-279252was then flowed over the bound ligands over a time course and a relativeindex of ‘on-rate’ (Ka) and ‘off-rate’ (Kd) was generated to calculatebinding affinity (K_(D)) of SL-279252 to each partner. Recombinant humanPD-1-Fc and OX40L-Fc were used as positive controls for binding. Thesecontrols have a relatively fast ‘on-rate’ and an equally fast‘off-rate’, resulting in low nanomolar binding affinities. Consistentwith these results, the ‘on-rate’ of SL-279252 to human PD-L1 was rapid,however the ‘off-rate’ was much lower, in fact ˜20-fold slower than the‘off-rate’ of recombinant PD-1-Fc, indicating that SL-279252 boundquickly and stably, with long on-target residence time (FIG. 14A). TheK_(D) of SL-279252 binding to human PD-L1 was calculated to be 2.08 nM,nearly identical to the observed K_(D) of BMS's OPDIVO (˜4 nM). TheK_(D) of SL-279252 binding to human PD-L2 was calculated to be 1.24 nM(FIG. 14B). SL-279252 bound with high affinity to human OX40 (246 pM),again with a fast ‘on-rate’ and slow ‘off-rate’ (FIG. 14C).

To further define the molecular characteristics of SL-279252, SPR wasperformed, analyzing the binding affinities of SL-279252 to chip-bound,Fcγ receptors FcγR1A and to the neonatal receptor, FcRn. The humanimmunoglobulin IgG1 was shown to bind with the highest affinities toFcγR1A, followed by FcRn, in addition to low-level binding to FcγR2b(FIG. 14C and FIG. 14D). SL-279252 did not bind to FcγR1A or FcγR2B, butdid bind to FcRn at 73 nM affinity (FIG. 14D and FIG. 14E). Withoutwishing to be bound by theory, this binding characteristic may beimportant to the fusion protein because FcRn is involved in IgGrecycling to the surface of a cell, thereby avoiding lysosomaldegradation, and potentially extending the in vivo half-life ofSL-279252. Summary data for SL-279252 binding affinities are including(FIG. 14F).

Next, surface plasmon resonance (SPR) analysis was performed todetermine the affinity by which a mutated SL-279252 construct containinga collagen V leader peptide and Fc region mutations to increase bindingto FcRn (named colPD1-FcRnOX40L) was examined for binding to hPD-L1,hPD-L1, hOX40 and various human Fc receptors (FIG. 14A to FIG. 14O).Specifically, polyhistidine-tagged versions of recombinant human PD-L1,PD-L2 and human OX40 was bound to ProteOn HTG tris-NTA chips (BIORAD).colPD1-FcRnOX40L was then flowed over the bound ligands over a timecourse and a relative index of ‘on-rate’ (Ka) and ‘off-rate’ (Kd) wasgenerated to calculate binding affinity (K_(D)) of colPD1-FcRnOX40L toeach partner. Recombinant human PD-1-Fc and OX40L-Fc were used aspositive controls for binding. These controls have a relatively fast‘on-rate’ and an equally fast ‘off-rate’, resulting in low nanomolarbinding affinities. Consistent with these results, the ‘on-rate’ ofcolPD1-FcRnOX40L to human PD-L1 was rapid, however the ‘off-rate’ wasmuch lower, in fact ˜10-fold slower than the ‘off-rate’ of recombinantPD-1-Fc, indicating that colPD1-FcRnOX40L bound quickly and stably, withlong on-target residence time (FIG. 14G). The K_(D) of colPD1-FcRnOX40Lbinding to human PD-L1 was calculated to be 6.35 nM, nearly identical tothe observed K_(D) of BMS's OPDIVO (˜4 nM). The K_(D) ofcolPD1-FcRnOX40L binding to human PD-L2 was calculated to be 7.93 nM(FIG. 14H). colPD1-FcRnOX40L bound with high affinity to human OX40(9.61 nM), again with a fast ‘on-rate’ and slow ‘off-rate’ (FIG. 14I).

To further define the molecular characteristics of colPD1-FcRnOX40L, SPRwas performed, analyzing the binding affinities of colPD1-FcRnOX40L tochip-bound, Fcγ receptors FcγR1A and to the neonatal receptor, FcRn. Thehuman immunoglobulin IgG1 was shown to bind with the highest affinitiesto FcγR1A, followed by FcRn, in addition to low-level binding to FcγR2b(FIG. 14J and FIG. 14K). colPD1-FcRnOX40L did not bind to FcγR1A orFcγR2B, but did bind to FcRn at 2.51 nM affinity (FIG. 14K). Withoutwishing to be bound by theory, this binding characteristic may beimportant to the fusion protein because FcRn is involved in IgGrecycling to the surface of a cell, thereby avoiding lysosomaldegradation, and potentially extending the in vivo half-life ofcolPD1-FcRnOX40L. Summary data for colPD1-FcRnOX40L binding affinitiesare including (FIG. 14L).

Additionally, the in vivo half-life of the purified SL-279252 was testedin C57BL/6 mice by injecting 200 μg of the protein by intra-peritonealinjection. Blood was then collected from treated animals by cardiacpuncture at 10 minutes, 30 minutes, 1 hour, 3, 6, 12 and 24 hours andallowed to clot for 2 hours at room temperature. The serum was thenassayed using a human IgG or OX40L specific ELISA as outlined above. Asshown in FIG. 14M, the serum half-life of SL-279252 in mice following asingle injection of 200 μg of protein was determined to be between 7-15hours. It is anticipated that constructs containing mutations toincrease binding affinity to FcRn will lead to longer half-life in vivo.

The slow off-rates detected by SPR suggested that SL-279252 may have alonger on-target (i.e. intratumoral) half-life than serum half life. Toinvestigate this question, immunocompromised NSG mice were implantedwith a PD-L1 negative HeLa (human cervical cancer) tumor on one flank,and with a PD-L1 expressing HeLa tumor on the opposite flank. Mice weretreated with single injections of 200 μg of SL-279252 and individualmice were sacrificed at defined time points. At the time of sacrifice,both HeLa tumors were excised and bisected. Half of the tumor wasdissociated and analyzed for SL-279252 binding by flow cytometry. Thisanalysis demonstrated that SL-279252 accumulated specifically in PD-L1positive, but not PD-L1 negative tumors. The concentration of SL-279252was observed to increase in the tumor up to 48 hours post treatment(FIG. 14N). Further, immunohistochemical analysis of the other half ofeach tumor demonstrated that significant staining for human OX40L waspresent 5 days post treatment, suggesting that SL-279252 was detectablein PD-L1 positive human tumors at least 5 days following a singletreatment (FIG. 14O).

Example 4. Additional Functional Characterization of Human PD-1-Fc-OX40L

The previous data indicated that SL-279252 binds to immobilized targetsat low nanomolar affinities and was detectable by multiple proteinassays. Additional analysis was carried out to determine whetherSL-279252 could bind its targets on the surface of living cells invitro. To assess SL-279252 binding to the human OX40 receptor, the humanAML T cell line Jurkat was engineered to overexpress OX40, creatingJurkat/hOX40 cells (verified by flow cytometry; FIG. 15A). To assessbinding to PD-L1, the Chinese hamster ovary cell line, CHO-K1, whichdoes not express human PD-L1, was transfected to stably express humanPD-L1 (FIG. 15B). To assess binding to human CD47, CHO-K1 cells weretransfected to stably express human CD47 (FIG. 15C).

CHO-K1 or CHO-K1-PD-L1 cells were then treated with increasing amountsof SL-279252 and analyzed by flow cytometry for the detection of thehuman OX40L domain using anti-human OX40L-APC antibodies. SL-279252 didnot bind to parental CHO-K1 cells since they expressed no detectablehuman PD-L1. However, nearly the entire population of CHO-K1-PD-L1 cellsshifted significantly, indicating that the human PD1 component ofSL-279252 was capable of binding its receptor on living cells (FIG.15D). Jurkat or Jurkat/OX40 cells were then treated with increasingamounts of SL-279252 and analyzed by flow cytometry for detection of thehuman OX40L domain using anti-human OX40L-APC antibodies. SL-279252 didnot bind parental Jurkat cells with high efficiency, since they expresslow amounts of human OX40. However, nearly the entire population ofJurkat/OX40 cells shifted significantly, indicating that the human OX40Lcomponent of SL-279252 was capable of binding its receptor on livingcells (FIG. 15E).

To investigate binding of another chimeric fusion protein, humanCD172a-Fc-OX40L, CHO-K1 or CHO-K1-CD47 cells were then treated withincreasing amounts of CD172a-Fc-OX40L and analyzed by flow cytometry forthe detection of the human OX40L domain using anti-human OX40L-APCantibodies. CD172a-Fc-OX40L did not bind to parental CHO-K1 cells sincethey expressed no detectable human CD47. However, nearly the entirepopulation of CHO-K1-PD-L1 cells shifted significantly, indicating thatthe human CD172a component of CD172a-Fc-OX40L was capable of binding itsreceptor on living cells (FIG. 15F). Jurkat or Jurkat/OX40 cells werethen treated with increasing amounts of CD172a-Fc-OX40L and analyzed byflow cytometry for detection of the human OX40L domain using anti-humanOX40L-APC antibodies. CD172a-Fc-OX40L did not bind parental Jurkat cellswith high efficiency, since they express low amounts of human OX40.However, nearly the entire population of Jurkat/OX40 cells shiftedsignificantly, indicating that the human OX40L component ofCD172a-Fc-OX40L was capable of binding its receptor on living cells(FIG. 15G).

Additionally, a number of human tumor cell lines were screened fordiffering levels of endogenous human PD-L1 expression by flow cytometry.A prostate cancer cell line (PC3) as PD-L1_(10W) and a lungadenocarcinoma cell line (HCC827) as PD-L1_(high) were identified (FIG.15H). The PC3 and HCC827 cells were incubated with increasing amounts ofSL-279252, and binding was detected using flow cytometry. SL-279252 didnot bind to PC3 cells (PD-L1_(low)) efficiently (FIG. 15I). However,SL-279252 bound significantly to HCC827 cells (PD-L1_(high)) in aconcentration dependent manner (FIG. 15J). This clearly indicated thatSL-279252 could bind both human OX40 and PD-L1 expressed on the cellsurface, which provided compelling evidence for its dual bindingfunctionality.

To expand upon these results, experiments were performed SL-279252binding to primary T cells isolated from peripheral blood mononuclearcells (PBMCs), induced for 2 days ex vivo with a chemical combinationknown to stimulate OX40 expression (phorbol 12-myristate 13-acetate;PMA, phytohemagglutinin; PHA, and lonomycin). As expected, a largeincrease in OX40 expression on CD4+ and CD8+ T cells was observedfollowing PMA/PHA/Ion treatment (FIG. 16A). Binding of SL-279252 to CD4+and CD8+ cells was confirmed using the methods described above (FIG.16B). It was noted that SL-279252 bound efficiently to human T cells(both CD4+ and CD8+).

A T cell activation/IL2 release assay was utilized to assess the extentthat PD-L1 expression on tumor cells inhibited T cell secretion of theanti-tumorigenic cytokine IL2 when the cells were co-cultured (FIG.16C). After 2 days, activated T cells were plated on irradiatedPD-L1_(10w) (PC3) and PD-Li_(high) (HCC827) expressing cancer cell linesin the presence or absence of SL-279252. Various readouts of T cellactivation were assessed for up to 1 week following initial T cellisolation, including IL2 secretion (FIG. 16D), proliferation andcytokine expression (FIG. 16E). Baseline levels of IL2 secretion (in theabsence of SL-279252) were significantly higher in PD-L11_(0W) PC3co-cultures than with PD-Li_(high) HCC827 cells 6 days after T cellisolation, suggesting that tumor PD-L1 expression either directly orindirectly suppressed the further activation of T cells, as determinedby IL2 secretion (FIG. 16D). The addition of SL-279252 to both PC3 andHCC827 co-cultures increased the IL2 secretion in a concentrationdependent manner. Specifically, the observed increase in IL-2 fromHCC827 co-cultures (PD-L1_(high)) from baseline (no SL-279252) to 5ug/mL of SL-279252 was 1.92-fold, compared to 1.27-fold when co-culturedwith PC3 cells (PD-L110).

Furthermore, additional characteristics of T cell activation wereanalyzed, including expression of the proliferation marker Ki67 (FIG.16E; top). Co-culture of activated T cells with PD-L1_(high) HCC827cells inhibited proliferation as compared to the level observed in theabsence of HCC827 cells (black line). The addition of SL-279252 to theco-culture increased Ki67 staining in both CD4+ and CD8+ T cells.Moreover, activated T cells expressed higher levels of the cytokinesIFNγ and TNFα when co-cultured on HCC827 cells than when T cells werecultured alone, possibly due to the secretion of other stimulatoryfactors by the tumor cells (FIG. 16E; bottom). The expression of thesecytokines increased significantly following treatment with SL-279252.

Altogether these data demonstrate, inter alia, that SL-279252 boundtightly to its partners PD-L1 and OX40 and was able to reverse PD-L1mediated T cell inhibition by PD-L1 positive human tumor cells in vitro.

Example 5. Construction and Characterization of Additional ChimericProteins

Additional constructs were generated which include: additional humanPD-1-Fc-OX40L constructs as well as human hCD172a-Fc-OX40L,hPD1-Fc-TL1A, hBTLA-Fc-OX40L, hTMIGD2-Fc-OX40L, hTIM3-Fc-OX40L,mPD1-Fc-GITRL, mPD1-Fc-41BBL, mPD1-Fc-TL1A, mCD172a-Fc-CD40L,hTIGIT-Fc-OX40L and canine PD-1-Fc-OX40L. Each of these constructs wascodon optimized for expression in Chinese Hamster Ovary (CHO) cells,transfected into CHO cells and individual clones were selected for highexpression. High expressing clones were then used for small-scalemanufacturing in stirred bioreactors in serum-free media and therelevant chimeric fusion proteins were purified with Protein A bindingresin columns. FIG. 17A shows a Western blot characterization of variouschimeric proteins including hCD172a-Fc-OX40L, hPD1-Fc-TL1A,hBTLA-Fc-OX40L, hTMIGD2-Fc-OX40L, hTIM3-Fc-OX40L, mPD1-Fc-GITRL,mPD1-Fc-41BBL, mPD1-Fc-TL1A, mCD172a-Fc-CD40L, hTIGIT-Fc-OX40L.

Binding assays were carried out to characterize the ability of thevarious human ECD-Fc-OX40L constructs to bind to hOX40. With respect tohX_(ECD)-Fc-OX40L, X refers to the ECD of each protein listed in thebracket on the left (with reference to FIG. 17B). FIG. 17B shows aschematic representation of the ELISA method used to detect binding ofhX_(ECD)-Fc-OX40L to hOX40. Recombinant hOX40 fused to human Fc(hOX40-hFc) was used to capture hX_(ECD)-Fc-OX40L in the culture media.Because the hOX40 fusion protein used to capture the target fusionproteins also contains a hIgG region, blocking was performed using anon-HRP conjugated anti-hIgG prior to incubation with the culturesupernatants containing the target fusion proteins. A rabbit polyclonalantibody to hIgG was used to detect the hIgG domain in the chimericprotein and subsequently detected using a horseradish peroxidase(HRP)-conjugated polyclonal antibody to rabbit IgG (H+L).

The binding of SL-279252 to cell surface expressed OX40 on Jurkat cellsby flow cytometry was compared to two negative control proteins whichare not expected to bind human OX40. These data demonstrate thatSL-279252 efficiently binds human OX40 (left panel), while neither humanPD1-Fc-TL1A or canine PD1-Fc-OX40L were observed to bind human OX40(FIG. 17C).

The human CD172a-Fc-OX40L construct was imported into the proteintertiary prediction software RaptorX to determine the tertiarystructure. The predicted tertiary structure is shown in FIG. 17D.

The codon-optimized DNA sequence of several chimeric fusion proteinswere synthesized and directionally cloned into pVITRO2, pcDNA3.4 andother expression vectors. Vectors were then either transiently or stablytransfected into CHO or 293 cells and individual clones were selectedfor high expression. For example, SL-279252 was produced from atransient transfection from 293 cells, purified by affinitychromatography to Protein A columns and evaluated by Coomassie staining,Western blot and quantitated as compared to a BCG standard (FIG. 17E).

In another example, CD172a-Fc-OX40L was produced from a transienttransfection from 293 cells, purified by affinity chromatography toProtein A columns and evaluated by Coomassie staining, Western blot andquantitated as compared to a BCG standard (FIG. 17F). In anotherexample, CD172a-Fc-CD40L was produced from a transient transfection from293 cells, purified by affinity chromatography to Protein A columns andevaluated by the Perkin Elmer LabChip system and quantitated as comparedto a BCG standard (FIG. 17G). In another example, human TIGIT-Fc-OX40Lwas produced from a transient transfection from 293 cells, purified byaffinity chromatography to Protein A columns and evaluated by Coomassiestaining, Western blot and quantitated as compared to a BCG standard(FIG. 17H).

The binding affinity of human CD172a-Fc-OX40L was evaluated by surfaceplasmon resonance (SPR) analysis to hCD47, hOX40 and various human Fcreceptors (FIG. 17I toFIG. 17M). Specifically, polyhistidine-taggedversions of recombinant human CD47 and human OX40 was bound to ProteOnHTG tris-NTA chips (BIORAD). CD172a-Fc-OX40L was then flowed over thebound ligands over a time course and a relative index of ‘on-rate’ (Ka)and ‘off-rate’ (Kd) was generated to calculate binding affinity (K_(D))of CD172a-Fc-OX40L to each partner. Recombinant human CD47-Fc andOX40L-Fc were used as positive controls for binding. These controls havea relatively fast ‘on-rate’ and an equally fast ‘off-rate’, resulting inlow nanomolar binding affinities. Consistent with these results, the‘on-rate’ of CD172a-Fc-OX40L to human CD47 was rapid, however the‘off-rate’ was much lower, in fact ˜40-fold slower than the ‘off-rate’of recombinant CD47-Fc, indicating that CD172a-Fc-OX40L bound quicklyand stably, with long on-target residence time (FIG. 17I). The K_(D) ofCD172a-Fc-OX40L binding to human CD47 was calculated to be 3.59 nM.CD172a-Fc-OX40L bound with high affinity to human OX40 (869 pM), againwith a fast ‘on-rate’ and slow ‘off-rate’ (FIG. 17J).

To further define the molecular characteristics of CD172a-Fc-OX40L, SPRwas performed, analyzing the binding affinities of CD172a-Fc-OX40L tochip-bound, Fcγ receptors FcγR1A and to the neonatal receptor, FcRn. Thehuman immunoglobulin IgG1 was shown to bind with the highest affinitiesto FcγR1A, followed by FcRn, in addition to low-level binding to FcγR2b(FIG. 17K and FIG. 17L). CD172a-Fc-OX40L did not bind to FcγR1A orFcγR2B, but did bind to FcRn at 790 nM affinity (FIG. 17L). Withoutwishing to be bound by theory, this binding characteristic may beimportant to the fusion protein because FcRn is involved in IgGrecycling to the surface of a cell, thereby avoiding lysosomaldegradation, and potentially extending the in vivo half-life ofCD172a-Fc-OX40L. Summary data for CD172a-Fc-OX40L binding affinities areincluding (FIG. 17M).

The codon-optimized DNA sequence of several additional chimeric fusionproteins were synthesized and directionally cloned into pVITRO2,pcDNA3.4 and other expression vectors. Vectors were then eithertransiently or stably transfected into CHO or 293 cells and individualclones were selected for high expression. For example, caninePD1-Fc-OX40L was produced from a transient transfection from 293 cells,purified by affinity chromatography to Protein A columns and evaluatedby Coomassie staining, Western blot and quantitated as compared to a BCGstandard (FIG. 17N). In another example, mouse PD1-Fc-OX40L was producedfrom a transient transfection from 293 cells, purified by affinitychromatography to Protein A columns and evaluated by Coomassie staining,Western blot and quantitated as compared to a BCG standard (FIG. 17O).In another example, mouse PD1-Fc-GITRL was produced from a transienttransfection from 293 cells, purified by affinity chromatography toProtein A columns and evaluated by Coomassie staining, Western blot andquantitated as compared to a BCG standard (FIG. 17P). In anotherexample, mouse PD1-Fc-41BBL was produced from a transient transfectionfrom 293 cells, purified by affinity chromatography to Protein A columnsand evaluated by Coomassie staining, Western blot and quantitated ascompared to a BCG standard (FIG. 17Q). In another example, mousePD1-Fc-TL1A was produced from a transient transfection from 293 cells,purified by affinity chromatography to Protein A columns and evaluatedby Coomassie staining, Western blot and quantitated as compared to a BCGstandard (FIG. 17R). In yet another example, CD115-Fc-CD40L was producedfrom a transient transfection from 293 cells, purified by affinitychromatography to Protein A columns and evaluated by Coomassie staining,Western blot and quantitated as compared to a BCG standard (FIG. 17S).

Each purified protein is characterized by ELISA assays to bind to themarker, e.g. the intended inhibitory ligand as well as the intendedcostimulatory receptor. For example, to test the binding of purifiedhuman PD-1-Fc-OX40L, recombinant PD-L1-Fc is adsorbed to microtiterplates and used to capture PD-1-Fc-OX40L. Any bound PD-1-Fc-OX40L isthen detected by using recombinant human OX40-Fc linked to biotin, whichis then detected in a chromogenic assay through binding withstreptravidin-HRP.

In addition, each purified protein has been characterized by flowcytometry to bind the intended inhibitory ligand as well as the intendedcostimulatory receptor. For example, human tumor cell lines arecharacterized for endogenous expression of PD-L1, which was found to beparticularly abundant on several human melanoma tumor cell lines. Thesesame tumor cell lines were shown to be negative for human OX40L.Following incubation with PD-1-Fc-OX40L, any bound chimeric fusionprotein is detected with human OX40L specific antibodies. Similarly,human Jurkat cells were transfected with human OX40 and shown to benegative for human PD-L1. Following incubation with the chimericPD-1-Fc-OX40L constructs, any bound complex is detected using anti-humanPD-L1 specific antibodies. A series of screening cell lines weregenerated in order to detect specific cell surface binding of eachchimeric fusion protein to its respective receptor/ligand, theseincluded: CHO-K1-CD47, CHO-K1-PD-L1, CHO-K1-HVEM, CHO-K1-HHLA2,CHO-K1-VISTA, CHO-K1-Gal9, HeLa-PD-L1, HeLa-CD47, HeLa-HVEM, HeLa-HHLA2,HeLa-VISTA, HeLa-Gal9.

To determine the functional activity of each receptor, in vitro T cellproliferation assays are performed in the presence of inhibitory ligandpositive human tumor cells. For example, human melanoma tumor cellsexpressing PD-L1 are pulsed with peptides specific for hen egg lysozyme(HEL) and incubated with human HEL specific T cells expressing OX40receptor. The proliferation of these cells is monitored in the presenceand absence of the PD-1-Fc-OX40L construct and found to be functionallyresponsive to the presence of the chimeric constructs. In a similarsystem, human tumors expressing HVEM, CD47, galectin-9, TIGIT receptorsor TMIGD2 receptors are used.

In some experiments, mouse PD-1-Fc-OX40L or mouse PD-1-Fc-TL1A are usedto treat murine tumors known to be positive for murine PD-L1 (includingB16-F10 melanoma, MC38 colon carcinoma and CT26 colon carcinoma). Inthese systems, established tumors are treated with purified chimericfusion proteins as compared to PD-1-Fc fusion proteins, anti-PD-1 oranti-PD-L1 monoclonal antibodies or anti-OX40 or anti-GITR monoclonalantibodies. In these experiments, the activity of the chimericconstructs is observed to lead to enhanced antigen-specific T cellresponses and increased rates of tumor rejection as compared to theindividual therapeutics. In some experiments, nucleic acid constructsencoding PD-1-Fc-OX40L or PD-1-Fc-TL1A are directly electroporated intoestablished tumors. In these experiments, the chimeric constructs areshown to lead to increased rates of tumor rejection as well as increasedtumor antigen specific CD8+ T cell proliferation detected both in theperipheral blood and within established tumors.

To determine the binding of purified chimeric fusion proteins to humantumor explants, fresh frozen human tumor samples are obtained andincubated with each chimeric fusion protein. Any bound fusion protein isdetected with anti-human OX40L and controlled against backgroundstaining by separate staining with anti-human OX40L.

To determine the molecular characteristics of each fusion protein,purified chimeric fusion proteins are characterized by size exclusionchromatography. This analysis is important because, for example, theOX40L ECD is known to form a homo-trimer, while the Fc region is knownto form a homo-dimer, while the inhibitory ligand binding receptor mayeither be monomeric (e.g. PD-1) or form homo-multimers (e.g. TIM3).Thus, there are several possibilities for the individual species thatmay be formed by these chimeric constructs. Further molecularcharacterization by mass spec, thermal stability, pH stability, physicalstability, charge profile, hydrophobicity, physical stability, buffercompatibility and solubility up to 100 mg/mL are also performed.

TABLE 1 Illustrative human Type I proteins which may be incorporatedinto the present compositions and methods include (as used herein“Entry” refers to the human Type I protein entry in the Uniprot databaseand “Entry name” refers to the human Type I protein entry in the Uniprotdatabase). Entry Entry name Protein names Gene names Length P044391A03_HUMAN HLA class I histocompatibility antigen, A-3 alpha chain (MHCclass I antigen A*3) HLA-A HLAA 365 P30456 1A43_HUMAN HLA class Ihistocompatibility antigen, A-43 alpha chain (Aw-43) (MHC class Iantigen A*43) HLA-A HLAA 365 P10316 1A69_HUMAN HLA class Ihistocompatibility antigen, A-69 alpha chain (Aw-69) (HLA class Ihistocompatibility antigen, HLA-A HLAA 365 A-28 alpha chain) (MHC classI antigen A*69) P30460 1B08_HUMAN HLA class I histocompatibilityantigen, B-8 alpha chain (MHC class I antigen B*8) HLA-B HLAB 362 Q953651B38_HUMAN HLA class I histocompatibility antigen, B-38 alpha chain(Bw-4) (MHC class I antigen B*38) HLA-B HLAB 362 P18464 1B51_HUMAN HLAclass I histocompatibility antigen, B-51 alpha chain (MHC class Iantigen B*51) HLA-B HLAB 362 P30495 1B56_HUMAN HLA class Ihistocompatibility antigen, B-56 alpha chain (Bw-22) (Bw-56) (MHC classI antigen B*56) HLA-B HLAB 362 P10319 1B58_HUMAN HLA class Ihistocompatibility antigen, B-58 alpha chain (Bw-58) (MHC class Iantigen B*58) HLA-B HLAB 362 P30501 1C02_HUMAN HLA class Ihistocompatibility antigen, Cw-2 alpha chain (MHC class I antigen Cw*2)HLA-C HLAC 366 P04222 1C03_HUMAN HLA class I histocompatibility antigen,Cw-3 alpha chain (MHC class I antigen Cw*3) HLA-C HLAC 366 Q9TNN71C05_HUMAN HLA class I histocompatibility antigen, Cw-5 alpha chain (MHCclass I antigen Cw*5) HLA-C HLAC 366 P10321 1C07_HUMAN HLA class Ihistocompatibility antigen, Cw-7 alpha chain (MHC class I antigen Cw*7)HLA-C HLAC 366 Q07000 1C15_HUMAN HLA class I histocompatibility antigen,Cw-15 alpha chain (MHC class I antigen Cw*15) HLA-C HLAC 366 Q956041C17_HUMAN HLA class I histocompatibility antigen, Cw-17 alpha chain(MHC class I antigen Cw*17) HLA-C D6S204 372 HLA-JY3 HLAC P137602B14_HUMAN HLA class II histocompatibility antigen, DRB1-4 beta chain(MHC class II antigen DRB1*4) (DR-4) (DR4) HLA-DRB1 266 Q9TQE02B19_HUMAN HLA class II histocompatibility antigen, DRB1-9 beta chain(MHC class II antigen DRB1*9) (DR-9) (DR9) HLA-DRB1 266 Q301672B1A_HUMAN HLA class II histocompatibility antigen, DRB1-10 beta chain(DRw10) (MHC class II antigen DRB1*10) HLA-DRB1 266 Q29974 2B1G_HUMANHLA class II histocompatibility antigen, DRB1-16 beta chain (MHC classII antigen DRB1*16) (DR-16) (DR16) HLA-DRB1 266 P01889 1B07_HUMAN HLAclass I histocompatibility antigen, B-7 alpha chain (MHC class I antigenB*7) HLA-B HLAB 362 P30462 1B14_HUMAN HLA class I histocompatibilityantigen, B-14 alpha chain (MHC class I antigen B*14) HLA-B HLAB 362P30464 1B15_HUMAN HLA class I histocompatibility antigen, B-15 alphachain (MHC class I antigen B*15) HLA-B HLAB 362 P03989 1B27_HUMAN HLAclass I histocompatibility antigen, B-27 alpha chain (MHC class Iantigen B*27) HLA-B HLAB 362 P18463 1B37_HUMAN HLA class Ihistocompatibility antigen, B-37 alpha chain (MHC class I antigen B*37)HLA-B HLAB 362 P30479 1B41_HUMAN HLA class I histocompatibility antigen,B-41 alpha chain (Bw-41) (MHC class I antigen B*41) HLA-B HLAB 362P30483 1B45_HUMAN HLA class I histocompatibility antigen, B-45 alphachain (Bw-45) (MHC class I antigen B*45) HLA-B HLAB 362 P304851B47_HUMAN HLA class I histocompatibility antigen, B-47 alpha chain(Bw-47) (MHC class I antigen B*47) HLA-B HLAB 362 P30487 1B49_HUMAN HLAclass I histocompatibility antigen, B-49 alpha chain (HLA class Ihistocompatibility antigen, HLA-B HLAB 362 B-21 alpha chain) (MHC classI antigen B*49) P30491 1B53_HUMAN HLA class I histocompatibilityantigen, B-53 alpha chain (Bw-53) (MHC class I antigen B*53) HLA-B HLAB362 Q29940 1B59_HUMAN HLA class I histocompatibility antigen, B-59 alphachain (MHC class I antigen B*59) HLA-B HLAB 362 P30498 1B78_HUMAN HLAclass I histocompatibility antigen, B-78 alpha chain (MHC class Iantigen B*78) HLA-B HLAB 362 P30499 1C01_HUMAN HLA class Ihistocompatibility antigen, Cw-1 alpha chain (MHC class I antigen Cw*1)HLA-C HLAC 366 P30505 1C08_HUMAN HLA class I histocompatibility antigen,Cw-8 alpha chain (MHC class I antigen Cw*8) HLA-C HLAC 366 P305081C12_HUMAN HLA class I histocompatibility antigen, Cw-12 alpha chain(MHC class I antigen Cw*12) HLA-C HLAC 366 P01912 2B13_HUMAN HLA classII histocompatibility antigen, DRB1-3 chain (Clone P2-beta-3) (MHC classII antigen DRB1*3) HLA-DRB1 266 Q30134 2B18_HUMAN HLA class IIhistocompatibility antigen, DRB1-8 beta chain (MHC class II antigenDRB1*8) HLA-DRB1 266 (DR-8) (DR8) (DRw8) Q95IE3 2B1C_HUMAN HLA class IIhistocompatibility antigen, DRB1-12 beta chain (MHC class II antigenHLA-DRB1 266 DRB1*12) (DR-12) (DR12) Q9BYF1 ACE2_HUMANAngiotensin-converting enzyme 2 (EC 3.4.17.23) (ACE-relatedcarboxypeptidase) ACE2 805 (Angiotensin-converting enzyme homolog)(ACEH) (Metalloprotease MPROT15) UNQ868/PRO1885 [Cleaved into: Processedangiotensin-converting enzyme 2] P16188 1A30_HUMAN HLA class Ihistocompatibility antigen, A-30 alpha chain (MHC class I antigen A*30)HLA-A HLAA 365 P16190 1A33_HUMAN HLA class I histocompatibility antigen,A-33 alpha chain (Aw-19) (Aw-33) (MHC class I HLA-A HLAA 365 antigenA*33) P01891 1A68_HUMAN HLA class I histocompatibility antigen, A-68alpha chain (Aw-68) (HLA class I HLA-A HLAA 365 histocompatibilityantigen, A-28 alpha chain) (MHC class I antigen A*68) Q29836 1B67_HUMANHLA class I histocompatibility antigen, B-67 alpha chain (MHC class Iantigen B*67) HLA-B HLAB 362 P13761 2B17_HUMAN HLA class IIhistocompatibility antigen, DRB1-7 beta chain (MHC class II antigenHLA-DRB1 266 DRB1*7) (DR-7) (DR7) Q5Y7A7 2B1D_HUMAN HLA class IIhistocompatibility antigen, DRB1-13 beta chain (MHC class II antigenHLA-DRB1 266 DRB1*13) (DR-13) (DR13) P13746 1A11_HUMAN HLA class Ihistocompatibility antigen, A-11 alpha chain (MHC class I antigen A*11)HLA-A HLAA 365 P05534 1A24_HUMAN HLA class I histocompatibility antigen,A-24 alpha chain (Aw-24) (HLA class I HLA-A HLAA 365 histocompatibilityantigen, A-9 alpha chain) (MHC class I antigen A*24) P30512 1A29_HUMANHLA class I histocompatibility antigen, A-29 alpha chain (Aw-19) (MHCclass I antigen A*29) HLA-A HLAA 365 P16189 1A31_HUMAN HLA class Ihistocompatibility antigen, A-31 alpha chain (MHC class I antigen A*31)HLA-A HLAA 365 P10314 1A32_HUMAN HLA class I histocompatibility antigen,A-32 alpha chain (MHC class I antigen A*32) HLA-A HLAA 365 Q048261B40_HUMAN HLA class I histocompatibility antigen, B-40 alpha chain(Bw-60) (MHC class I antigen B*40) HLA-B HLAB 362 P30484 1B46_HUMAN HLAclass I histocompatibility antigen, B-46 alpha chain (Bw-46) (MHC classI antigen B*46) HLA-B HLAB 362 P30486 1B48_HUMAN HLA class Ihistocompatibility antigen, B-48 alpha chain (Bw-48) (MHC class Iantigen B*48) HLA-B HLAB 362 P30490 1B52_HUMAN HLA class Ihistocompatibility antigen, B-52 alpha chain (Bw-52) (HLA class Ihistocompatibility HLA-B HLAB 362 antigen, B-5 alpha chain) (MHC class Iantigen B*52) Q31612 1B73_HUMAN HLA class I histocompatibility antigen,B-73 alpha chain (MHC class I antigen B*73) HLA-B HLAB 363 Q316101B81_HUMAN HLA class I histocompatibility antigen, B-81 alpha chain(B′DT) (MHC class I antigen B*81) HLA-B HLAB 362 Q29960 1C16_HUMAN HLAclass I histocompatibility antigen, Cw-16 alpha chain (MHC class Iantigen Cw*16) HLA-C HLAC 366 Q29865 1C18_HUMAN HLA class Ihistocompatibility antigen, Cw-18 alpha chain (MHC class I antigenCw*18) HLA-C HLAC 366 Q9GIY3 2B1E_HUMAN HLA class II histocompatibilityantigen, DRB1-14 beta chain (MHC class II antigen HLA-DRB1 266 DRB1*14)(DR-14) (DR14) P30443 1A01_HUMAN HLA class I histocompatibility antigen,A-1 alpha chain (MHC class I antigen A*1) HLA-A HLAA 365 P018921A02_HUMAN HLA class I histocompatibility antigen, A-2 alpha chain (MHCclass I antigen A*2) HLA-A HLAA 365 P30447 1A23_HUMAN HLA class Ihistocompatibility antigen, A-23 alpha chain (HLA class Ihistocompatibility HLA-A HLAA 365 antigen, A-9 alpha chain) (MHC class Iantigen A*23) P18462 1A25_HUMAN HLA class I histocompatibility antigen,A-25 alpha chain (HLA class I histocompatibility HLA-A HLAA 365 antigen,A-10 alpha chain) (MHC class I antigen A*25) P30450 1A26_HUMAN HLA classI histocompatibility antigen, A-26 alpha chain (MHC class I antigenA*26) HLA-A HLAA 365 P30453 1A34_HUMAN HLA class I histocompatibilityantigen, A-34 alpha chain (Aw-34) (HLA class I HLA-A HLAA 365histocompatibility antigen, A-10 alpha chain) (MHC class I antigen A*34)P30457 1A66_HUMAN HLA class I histocompatibility antigen, A-66 alphachain (Aw-66) (HLA class I HLA-A HLAA 365 histocompatibility antigen,A-10 alpha chain) (MHC class I antigen A*66) Q09160 1A80_HUMAN HLA classI histocompatibility antigen, A-80 alpha chain (Aw-80) (HLA class IHLA-A HLAA 365 histocompatibility antigen, A-1 alpha chain) (MHC class Iantigen A*80) P30461 1B13_HUMAN HLA class I histocompatibility antigen,B-13 alpha chain (MHC class I antigen B*13) HLA-B HLAB 362 P304661B18_HUMAN HLA class I histocompatibility antigen, B-18 alpha chain (MHCclass I antigen B*18) HLA-B HLAB 362 P30685 1B35_HUMAN HLA class Ihistocompatibility antigen, B-35 alpha chain (MHC class I antigen B*35)HLA-B HLAB 362 P30475 1B39_HUMAN HLA class I histocompatibility antigen,B-39 alpha chain (MHC class I antigen B*39) HLA-B HLAB 362 P304801B42_HUMAN HLA class I histocompatibility antigen, B-42 alpha chain (MHCclass I antigen B*42) HLA-B HLAB 362 P30481 1B44_HUMAN HLA class Ihistocompatibility antigen, B-44 alpha chain (Bw-44) (MHC class Iantigen B*44) HLA-B HLAB 362 P30488 1B50_HUMAN HLA class Ihistocompatibility antigen, B-50 alpha chain (Bw-50) (HLA class Ihistocompatibility HLA-B HLAB 362 antigen, B-21 alpha chain) (MHC classI antigen B*50) P30492 1B54_HUMAN HLA class I histocompatibilityantigen, B-54 alpha chain (Bw-22) (Bw-54) (MHC class I antigen B*54)HLA-B HLAB 362 P18465 1B57_HUMAN HLA class I histocompatibility antigen,B-57 alpha chain (Bw-57) (MHC class I antigen B*57) HLA-B HLAB 362Q29718 1B82_HUMAN HLA class I histocompatibility antigen, B-82 alphachain (MHC class I antigen B*82) HLA-B HLAB 362 P30504 1C04_HUMAN HLAclass I histocompatibility antigen, Cw-4 alpha chain (MHC class Iantigen Cw*4) HLA-C HLAC 366 Q29963 1C06_HUMAN HLA class Ihistocompatibility antigen, Cw-6 alpha chain (MHC class I antigen Cw*6)HLA-C HLAC 366 P30510 1C14_HUMAN HLA class I histocompatibility antigen,Cw-14 alpha chain (MHC class I antigen Cw*14) HLA-C HLAC 366 P042292B11_HUMAN HLA class II histocompatibility antigen, DRB1-1 beta chain(MHC class II antigen HLA-DRB1 266 DRB1*1) (DR-1) (DR1) P200392B1B_HUMAN HLA class II histocompatibility antigen, DRB1-11 beta chain(DR-5) (DR5) (DRw11) (MHC HLA-DRB1 266 class II antigen DRB1*11) P019112B1F_HUMAN HLA class II histocompatibility antigen, DRB1-15 beta chain(DW2.2/DR2.2) (MHC class HLA-DRB1 HLA-DRB2 266 II antigen DRB1*15)O14672 ADA10_HUMAN Disintegrin and metalloproteinase domain-containingprotein 10 (ADAM 10) (EC ADAM10 KUZ 748 3.4.24.81) (CDw156) (Kuzbanianprotein homolog) (Mammalian disintegrin- MADM metalloprotease) (CDantigen CD156c) Q13444 ADA15_HUMAN Disintegrin and metalloproteinasedomain-containing protein 15 (ADAM 15) (EC 3.4.24.—) ADAM15 MDC15 863(Metalloprotease RGD disintegrin protein) (Metalloproteinase-like,disintegrin-like, and cysteine-rich protein 15) (MDC-15) (Metargidin)O75077 ADA23_HUMAN Disintegrin and metalloproteinase domain-containingprotein 23 (ADAM 23) ADAM23 MDC3 832 (Metalloproteinase-like,disintegrin-like, and cysteine-rich protein 3) (MDC-3) P30455 1A36_HUMANHLA class I histocompatibility antigen, A-36 alpha chain (Aw-36) (MHCclass I antigen A*36) HLA-A HLAA 365 P30459 1A74_HUMAN HLA class Ihistocompatibility antigen, A-74 alpha chain (Aw-19) (Aw-74) (MHC classI HLA-A HLAA 365 antigen A*74) P30493 1B55_HUMAN HLA class Ihistocompatibility antigen, B-55 alpha chain (Bw-55) (HLA class I HLA-BHLAB 362 histocompatibility antigen, B-12 alpha chain) (MHC class Iantigen B*55) CDABP0067 O43184 ADA12_HUMAN Disintegrin andmetalloproteinase domain-containing protein 12 (ADAM 12) (EC 3.4.24.—)ADAM12 MLTN 909 (Meltrin-alpha) UNQ346/PRO545 Q9Y3Q7 ADA18_HUMANDisintegrin and metalloproteinase domain-containing protein 18 (ADAM 18)ADAM18 TMDC3 739 (Transmembrane metalloproteinase-like,disintegrin-like, and cysteine-rich protein III) UNQ858/PRO1867 (tMDCIII) Q9H013 ADA19_HUMAN Disintegrin and metalloproteinasedomain-containing protein 19 (ADAM 19) (EC 3.4.24.—) ADAM19 MLTNB FKSG34955 (Meltrin-beta) (Metalloprotease and disintegrin dendritic antigenmarker) (MADDAM) Q9UKF5 ADA29_HUMAN Disintegrin and metalloproteinasedomain-containing protein 29 (ADAM 29) (Cancer/testis ADAM29 820 antigen73) (CT73) Q8TC27 ADA32_HUMAN Disintegrin and metalloproteinasedomain-containing protein 32 (ADAM 32) ADAM32 787 UNQ5982/PRO21340Q9BZ11 ADA33_HUMAN Disintegrin and metalloproteinase domain-containingprotein 33 (ADAM 33) (EC 3.4.24.—) ADAM33 C20orf153 813 UNQ873/PRO1891P05067 A4_HUMAN Amyloid beta A4 protein (ABPP) (APPI) (APP) (Alzheimerdisease amyloid protein) APP A4 AD1 770 (Amyloid precursor protein)(Beta-amyloid precursor protein) (Cerebral vascular amyloid peptide)(CVAP) (PreA4) (Protease nexin-II) (PN-II) [Cleaved into: N-APP; SolubleAPP- alpha (S-APP-alpha); Soluble APP-beta (S-APP-beta); C99;Beta-amyloid protein 42 (Beta-APP42); Beta-amyloid protein 40(Beta-APP40); C83; P3(42); P3(40); C80; Gamma-secretase C-terminalfragment 59 (Amyloid intracellular domain 59) (AICD-59) (AID(59))(Gamma-CTF(59)); Gamma-secretase C-terminal fragment 57 (Amyloidintracellular domain 57) (AICD-57) (AID(57)) (Gamma-CTF(57));Gamma-secretase C- terminal fragment 50 (Amyloid intracellular domain50) (AICD-50) (AID(50)) (Gamma- CTF(50)); C31] P12821 ACE_HUMANAngiotensin-converting enzyme (ACE) (EC 3.2.1.—) (EC 3.4.15.1)(Dipeptidyl ACE DCP DCP1 1306 carboxypeptidase I) (Kininase II) (CDantigen CD143) [Cleaved into: Angiotensin- converting enzyme, solubleform] Q04771 ACVR1_HUMAN Activin receptor type-1 (EC 2.7.11.30) (Activinreceptor type I) (ACTR-I) (Activin receptor- ACVR1 ACVRLK2 509 likekinase 2) (ALK-2) (Serine/threonine-protein kinase receptor R1) (SKR1)(TGF-B superfamily receptor type I) (TSR-I) Q8NER5 ACV1C_HUMAN Activinreceptor type-1C (EC 2.7.11.30) (Activin receptor type IC) (ACTR-IC)(Activin ACVR1C ALK7 493 receptor-like kinase 7) (ALK-7) Q9H2U9ADAM7_HUMAN Disintegrin and metalloproteinase domain-containing protein7 (ADAM 7) (Sperm ADAM7 GP83 754 maturation-related glycoprotein GP-83)P36896 ACV1B_HUMAN Activin receptor type-1B (EC 2.7.11.30) (Activinreceptor type IB) (ACTR-IB) (Activin ACVR1B ACVRLK4 ALK4 505receptor-like kinase 4) (ALK-4) (Serine/threonine-protein kinasereceptor R2) (SKR2) O75078 ADA11_HUMAN Disintegrin and metalloproteinasedomain-containing protein 11 (ADAM 11) ADAM11 MDC 769(Metalloproteinase-like, disintegrin-like, and cysteine-rich protein)(MDC) P78536 ADA17_HUMAN Disintegrin and metalloproteinasedomain-containing protein 17 (ADAM 17) (EC ADAM17 CSVP TACE 8243.4.24.86) (Snake venom-like protease) (TNF-alpha convertase)(TNF-alpha-converting enzyme) (CD antigen CD156b) Q9P0K1 ADA22_HUMANDisintegrin and metalloproteinase domain-containing protein 22 (ADAM 22)ADAM22 MDC2 906 (Metalloproteinase-disintegrin ADAM22-3)(Metalloproteinase-like, disintegrin-like, and cysteine-rich protein 2)Q9UKQ2 ADA28_HUMAN Disintegrin and metalloproteinase domain-containingprotein 28 (ADAM 28) (EC 3.4.24.—) ADAM28 ADAM23 775 (Epididymalmetalloproteinase-like, disintegrin-like, and cysteine-rich protein II)(eMDC II) MDCL (Metalloproteinase-like, disintegrin-like, andcysteine-rich protein L) (MDC-L) Q9UKF2 ADA30_HUMAN Disintegrin andmetalloproteinase domain-containing protein 30 (ADAM 30) (EC 3.4.24.—)ADAM30 790 UNQ2509/PRO5997 P19021 AMD_HUMAN Peptidyl-glycinealpha-amidating monooxygenase (PAM) [Includes: Peptidylglycine alpha-PAM 973 hydroxylating monooxygenase (PHM) (EC 1.14.17.3);Peptidyl-alpha-hydroxyglycine alpha-amidating lyase (EC 4.3.2.5)(Peptidylamidoglycolate lyase) (PAL)] Q86SJ2 AMGO2_HUMANAmphoterin-induced protein 2 (AMIGO-2) (Alivin-1) (Differentiallyexpressed in gastric AMIGO2 ALI1 522 adenocarcinomas) (DEGA) Q16671AMHR2_HUMAN Anti-Muellerian hormone type-2 receptor (EC 2.7.11.30)(Anti-Muellerian hormone type II AMHR2 AMHR 573 receptor) (AMH type IIreceptor) (MIS type II receptor) (MISRII) (MRII) MISR2 P37023ACVL1_HUMAN Serine/threonine-protein kinase receptor R3 (SKR3) (EC2.7.11.30) (Activin receptor-like ACVRL1 ACVRLK1 503 kinase 1) (ALK-1)(TGF-B superfamily receptor type I) (TSR-I) ALK1 Q13443 ADAM9_HUMANDisintegrin and metalloproteinase domain-containing protein 9 (ADAM 9)(EC 3.4.24.—) ADAM9 KIAA0021 819 (Cellular disintegrin-related protein)(Meltrin-gamma) MCMP MDC9 (Metalloprotease/disintegrin/cysteine-richprotein 9) (Myeloma cell metalloproteinase) MLTNG O43506 ADA20_HUMANDisintegrin and metalloproteinase domain-containing protein 20 (ADAM 20)(EC 3.4.24.—) ADAM20 726 Q9UKJ8 ADA21_HUMAN Disintegrin andmetalloproteinase domain-containing protein 21 (ADAM 21) (EC 3.4.24.—)ADAM21 722 Q99965 ADAM2_HUMAN Disintegrin and metalloproteinasedomain-containing protein 2 (ADAM 2) (Cancer/testis ADAM2 FTNB 735antigen 15) (CT15) (Fertilin subunit beta) (PH-30) (PH30) (PH30-beta)P78325 ADAM8_HUMAN Disintegrin and metalloproteinase domain-containingprotein 8 (ADAM 8) (EC 3.4.24.—) ADAM8 MS2 824 (Cell surface antigenMS2) (CD antigen CD156a) Q9H6X2 ANTR1_HUMAN Anthrax toxin receptor 1(Tumor endothelial marker 8) ANTXR1 ATR 564 TEM8 P58335 ANTR2_HUMANAnthrax toxin receptor 2 (Capillary morphogenesis gene 2 protein)(CMG-2) ANTXR2 CMG2 489 Q86WK6 AMGO1_HUMAN Amphoterin-induced protein 1(AMIGO-1) (Alivin-2) AMIGO1 ALI2 493 AMIGO KIAA1163 P16066 ANPRA_HUMANAtrial natriuretic peptide receptor 1 (EC 4.6.1.2) (Atrial natriureticpeptide receptor type A) NPR1 ANPRA 1061 (ANP-A) (ANPR-A) (NPR-A)(Guanylate cyclase A) (GC-A) Q6UXC1 AEGP_HUMAN Apical endosomalglycoprotein (MAM domain-containing protein 4) MAMDC4 AEGP 1216UNQ3001/PRO9742 Q9BXJ7 AMNLS_HUMAN Protein amnionless AMN 453UNQ513/PRO1028 P20594 ANPRB_HUMAN Atrial natriuretic peptide receptor 2(EC 4.6.1.2) (Atrial natriuretic peptide receptor type B) NPR2 ANPRB1047 (ANP-B) (ANPR-B) (NPR-B) (Guanylate cyclase B) (GC-B) Q8J025APCD1_HUMAN Protein APCDD1 (Adenomatosis polyposis coli down-regulated 1protein) APCDD1 DRAPC1 514 FP7019 P51693 APLP1_HUMAN Amyloid-likeprotein 1 (APLP) (APLP-1) [Cleaved into: C30] APLP1 650 Q9UM73 ALK_HUMANALK tyrosine kinase receptor (EC 2.7.10.1) (Anaplastic lymphoma kinase)(CD antigen CD246) ALK 1620 A6NF34 ANTRL_HUMAN Anthrax toxinreceptor-like ANTXRL 631 Q86WK7 AMGO3_HUMAN Amphoterin-induced protein 3(AMIGO-3) (Alivin-3) AMIGO3 ALI3 504 KIAA1851 UNQ6084/PRO20089 P17342ANPRC_HUMAN Atrial natriuretic peptide receptor 3 (Atrial natriureticpeptide clearance receptor) (Atrial NPR3 ANPRC 541 natriuretic peptidereceptor type C) (ANP-C) (ANPR-C) (NPR-C) C5orf23 NPRC Q06481APLP2_HUMAN Amyloid-like protein 2 (APLP-2) (APPH) (Amyloid proteinhomolog) (CDEI box-binding protein) (CDEBP) APLP2 APPL2 763 Q13705AVR2B_HUMAN Activin receptor type-2B (EC 2.7.11.30) (Activin receptortype IIB) (ACTR-IIB) ACVR2B 512 P35613 BASI_HUMAN Basigin (5F7)(Collagenase stimulatory factor) (Extracellular matrix metalloproteinaseBSG 385 inducer) (EMMPRIN) (Leukocyte activation antigen M6) (OK bloodgroup antigen) (Tumor UNQ6505/PRO21383 cell-derived collagenasestimulatory factor) (TCSF) (CD antigen CD147) P50895 BCAM_HUMAN Basalcell adhesion molecule (Auberger B antigen) (B-CAM cell surfaceglycoprotein) BCAM LU MSK19 628 (F8/G253 antigen) (Lutheran antigen)(Lutheran blood group glycoprotein) (CD antigen CD239) O75882 ATRN_HUMANAttractin (DPPT-L) (Mahogany homolog) ATRN KIAA0548 1429 MGCA Q9Y5Z0BACE2_HUMAN Beta-secretase 2 (EC 3.4.23.45) (Aspartic-like protease 56kDa) (Aspartyl protease 1) BACE2 AEPLC 518 (ASP1) (Asp 1) (Beta-siteamyloid precursor protein cleaving enzyme 2) (Beta-site APP ALP56 ASP21CDA13 cleaving enzyme 2) (Down region aspartic protease) (DRAP)(Memapsin-1) (Membrane- UNQ418/PRO852 associated aspartic protease 1)(Theta-secretase) Q13145 BAMBI_HUMAN BMP and activin membrane-boundinhibitor homolog (Non-metastatic gene A protein) BAMBI NMA 260(Putative transmembrane protein NMA) P36894 BMR1A_HUMAN Bonemorphogenetic protein receptor type-1A (BMP type-1A receptor) (BMPR-1A)(EC BMPR1A ACVRLK3 532 2.7.11.30) (Activin receptor-like kinase 3)(ALK-3) (Serine/threonine-protein kinase ALK3 receptor R5) (SKR5) (CDantigen CD292) P56817 BACE1_HUMAN Beta-secretase 1 (EC 3.4.23.46)(Aspartyl protease 2) (ASP2) (Asp 2) (Beta-site amyloid BACE1 BACEKIAA1149 501 precursor protein cleaving enzyme 1) (Beta-site APPcleaving enzyme 1) (Memapsin-2) (Membrane-associated aspartic protease2) Q5VV63 ATRN1_HUMAN Attractin-like protein 1 ATRNL1 KIAA0534 1379P27037 AVR2A_HUMAN Activin receptor type-2A (EC 2.7.11.30) (Activinreceptor type IIA) (ACTR-IIA) (ACTRIIA) ACVR2A ACVR2 513 Q9BWV1BOC_HUMAN Brother of CDO (Protein BOC) BOC 1114 UNQ604/PRO1190 O00238BMR1B_HUMAN Bone morphogenetic protein receptor type-1B (BMP type-1Breceptor) (BMPR-1B) (EC BMPR1B 502 2.7.11.30) (CD antigen CDw293) O00481BT3A1_HUMAN Butyrophilin subfamily 3 member A1 (CD antigen CD277) BTN3A1BTF5 513 Q7Z6A9 BTLA_HUMAN B- and T-lymphocyte attenuator (B- andT-lymphocyte-associated protein) (CD antigen CD272) BTLA 289 Q96KV6BT2A3_HUMAN Putative butyrophilin subfamily 2 member A3 BTN2A3P BTN2A3586 P78410 BT3A2_HUMAN Butyrophilin subfamily 3 member A2 BTN3A2 BT3.2334 BTF3 BTF4 Q6UXE8 BTNL3_HUMAN Butyrophilin-like protein 3(Butyrophilin-like receptor) BTNL3 BTNLR 466 COLF4100 UNQ744/PRO1472Q6UXG8 BTNL9_HUMAN Butyrophilin-like protein 9 BTNL9 535 UNQ1900/PRO4346Q5SY80 CA101_HUMAN Uncharacterized protein C1orf101 C1orf101 951 F2Z333CA233_HUMAN Fibronectin type-III domain-containing transmembrane proteinC1orf233 C1orf233 226 Q13410 BT1A1_HUMAN Butyrophilin subfamily 1 memberA1 (BT) BTN1A1 BTN 526 Q8WVV5 BT2A2_HUMAN Butyrophilin subfamily 2member A2 BTN2A2 BT2.2 BTF2 523 O00478 BT3A3_HUMAN Butyrophilinsubfamily 3 member A3 BTN3A3 BTF3 584 Q6UX41 BTNL8_HUMANButyrophilin-like protein 8 BTNL8 500 UNQ702/PRO1347 Q6UWJ8 C16L2_HUMANCD164 sialomucin-like 2 protein CD164L2 174 UNQ6122/PRO20044 P55289CAD12_HUMAN Cadherin-12 (Brain cadherin) (BR-cadherin) (Neural typecadherin 2) (N-cadherin 2) CDH12 794 Q9UJ99 CAD22_HUMAN Cadherin-22(Pituitary and brain cadherin) (PB-cadherin) CDH22 C20orf25 828 Q9H251CAD23_HUMAN Cadherin-23 (Otocadherin) CDH23 KIAA1774 3354 KIAA1812UNQ1894/PRO4340 Q8IXH8 CAD26_HUMAN Cadherin-like protein 26(Cadherin-like protein VR20) CDH26 852 P19022 CADH2_HUMAN Cadherin-2(CDw325) (Neural cadherin) (N-cadherin) (CD antigen CD325) CDH2 CDHNNCAD 906 P55285 CADH6_HUMAN Cadherin-6 (Kidney cadherin) (K-cadherin)CDH6 790 Q9ULB5 CADH7_HUMAN Cadherin-7 CDH7 CDH7L1 785 P55286CADH8_HUMAN Cadherin-8 CDH8 799 Q9ULX7 CAH14_HUMAN Carbonic anhydrase 14(EC 4.2.1.1) (Carbonate dehydratase XIV) (Carbonic anhydrase CA14 337XIV) (CA-XIV) UNQ690/PRO1335 Q5VU97 CAHD1_HUMAN VWFA and cachedomain-containing protein 1 (Cache domain-containing protein 1) CACHD1KIAA1573 VWCD1 1274 P27824 CALX_HUMAN Calnexin (IP90) (Majorhistocompatibility complex class I antigen-binding protein p88) (p90)CANX 592 Q13873 BMPR2_HUMAN Bone morphogenetic protein receptor type-2(BMP type-2 receptor) (BMPR-2) (EC BMPR2 PPH1 1038 2.7.11.30) (Bonemorphogenetic protein receptor type II) (BMP type II receptor) (BMPR-II)Q7KYR7 BT2A1_HUMAN Butyrophilin subfamily 2 member A1 BTN2A1 BT2.1 BTF1527 P35070 BTC_HUMAN Probetacellulin [Cleaved into: Betacellulin (BTC)]BTC 178 Q86VB7 C163A_HUMAN Scavenger receptor cysteine-rich type 1protein M130 (Hemoglobin scavenger receptor) CD163 M130 1156 (CD antigenCD163) [Cleaved into: Soluble CD163 (sCD163)] Q8TCZ2 C99L2_HUMAN CD99antigen-like protein 2 (MIC2-like protein 1) (CD antigen CD99) CD99L2MIC2L1 262 UNQ1964/PRO4486 Q8IZS8 CA2D3_HUMAN Voltage-dependent calciumchannel subunit alpha-2/delta-3 (Voltage-gated calcium CACNA2D3 1091channel subunit alpha-2/delta-3) [Cleaved into: Voltage-dependentcalcium channel subunit alpha-2-3; Voltage-dependent calcium channelsubunit delta-3] Q7Z3S7 CA2D4_HUMAN Voltage-dependent calcium channelsubunit alpha-2/delta-4 (Voltage-gated calcium CACNA2D4 1137 channelsubunit alpha-2/delta-4) [Cleaved into: Voltage-dependent calciumchannel subunit alpha-2-4; Voltage-dependent calcium channel subunitdelta-4] Q9Y6N8 CAD10_HUMAN Cadherin-10 (T2-cadherin) CDH10 788 Q12864CAD17_HUMAN Cadherin-17 (Intestinal peptide-associated transporterHPT-1) (Liver-intestine cadherin) CDH17 832 (LI-cadherin) P55283CADH4_HUMAN Cadherin-4 (Retinal cadherin) (R-CAD) (R-cadherin) CDH4 916P33151 CADH5_HUMAN Cadherin-5 (7B4 antigen) (Vascular endothelialcadherin) (VE-cadherin) (CD antigen CD144) CDH5 784 Q8NFZ8 CADM4_HUMANCell adhesion molecule 4 (Immunoglobulin superfamily member 4C) (IgSF4C)(Nectin-like CADM4 IGSF4C 388 protein 4) (NECL-4) (TSLC1-like protein 2)NECL4 TSLL2 Q9NPY3 C1QR1_HUMAN Complement component C1q receptor(C1q/MBL/SPA receptor) (C1qR) (C1qR(p)) CD93 C1QR1 MXRA4 652 (C1qRp)(CDw93) (Complement component 1 q subcomponent receptor 1) (Matrix-remodeling-associated protein 4) (CD antigen CD93) Q9NY47 CA2D2_HUMANVoltage-dependent calcium channel subunit alpha-2/delta-2 (Voltage-gatedcalcium CACNA2D2 KIAA0558 1150 channel subunit alpha-2/delta-2) [Cleavedinto: Voltage-dependent calcium channel subunit alpha-2-2;Voltage-dependent calcium channel subunit delta-2] Q8N3J6 CADM2_HUMANCell adhesion molecule 2 (Immunoglobulin superfamily member 4D) (IgSF4D)(Nectin-like CADM2 IGSF4D NECL3 435 protein 3) (NECL-3) (Synaptic celladhesion molecule 2) (SynCAM 2) Q13634 CAD18_HUMAN Cadherin-18(Cadherin-14) CDH18 CDH14 790 A8MVZ5 BTNLA_HUMAN Butyrophilin-likeprotein 10 BTNL10 291 Q9NR16 C163B_HUMAN Scavenger receptorcysteine-rich type 1 protein M160 (CD163 antigen-like 1) (CD antigenCD163b) CD163L1 CD163B M160 1453 UNQ6434/PRO23202 P54289 CA2D1_HUMANVoltage-dependent calcium channel subunit alpha-2/delta-1 (Voltage-gatedcalcium CACNA2D1 1103 channel subunit alpha-2/delta-1) [Cleaved into:Voltage-dependent calcium channel CACNL2A CCHL2A subunit alpha-2-1;Voltage-dependent calcium channel subunit delta-1] MHS3 Q86UP0CAD24_HUMAN Cadherin-24 CDH24 CDH11L 819 UNQ2834/PRO34009 Q9BY67CADM1_HUMAN Cell adhesion molecule 1 (Immunoglobulin superfamily member4) (IgSF4) (Nectin-like CADM1 IGSF4 442 protein 2) (NECL-2)(Spermatogenic immunoglobulin superfamily) (SgIgSF) (Synaptic cellIGSF4A NECL2 adhesion molecule) (SynCAM) (Tumor suppressor in lungcancer 1) (TSLC-1) SYNCAM TSLC1 Q9HBT6 CAD20_HUMAN Cadherin-20 CDH20CDH7L3 801 Q16790 CAH9_HUMAN Carbonic anhydrase 9 (EC 4.2.1.1)(Carbonate dehydratase IX) (Carbonic anhydrase IX) CA9 G250 MN 459(CA-IX) (CAIX) (Membrane antigen MN) (P54/58N) (Renal cellcarcinoma-associated antigen G250) (RCC-associated antigen G250) (pMW1)O75976 CBPD_HUMAN Carboxypeptidase D (EC 3.4.17.22)(Metallocarboxypeptidase D) (gp180) CPD 1380 P55287 CAD11_HUMANCadherin-11 (OSF-4) (Osteoblast cadherin) (OB-cadherin) CDH11 796 P55291CAD15_HUMAN Cadherin-15 (Cadherin-14) (Muscle cadherin) (M-cadherin)CDH15 CDH14 CDH3 814 O75309 CAD16_HUMAN Cadherin-16 (Kidney-specificcadherin) (Ksp-cadherin) CDH16 829 UNQ695/PRO1340 Q9H159 CAD19_HUMANCadherin-19 CDH19 CDH7L2 772 UNQ478/PRO941 P12830 CADH1_HUMAN Cadherin-1(CAM 120/80) (Epithelial cadherin) (E-cadherin) (Uvomorulin) (CD antigenCDH1 CDHE UVO 882 CD324) [Cleaved into: E-Cad/CTF1; E-Cad/CTF2;E-Cad/CTF3] P22223 CADH3_HUMAN Cadherin-3 (Placental cadherin)(P-cadherin) CDH3 CDHP 829 Q9ULB4 CADH9_HUMAN Cadherin-9 CDH9 789 Q8N126CADM3_HUMAN Cell adhesion molecule 3 (Brain immunoglobulin receptor)(Immunoglobulin superfamily CADM3 IGSF4B 398 member 4B) (IgSF4B)(Nectin-like protein 1) (NECL-1) (Synaptic cell adhesion molecule NECL1SYNCAM3 TSLL1 3) (SynCAM3) (TSLC1-like protein 1) (TSLL1) UNQ225/PRO258O43570 CAH12_HUMAN Carbonic anhydrase 12 (EC 4.2.1.1) (Carbonatedehydratase XII) (Carbonic anhydrase CA12 354 XII) (CA-XII) (Tumorantigen HOM-RCC-3.1.3) P15813 CD1D_HUMAN Antigen-presenting glycoproteinCD1d (R3G1) (CD antigen CD1d) CD1D 335 Q9BZW8 CD244_HUMAN Natural killercell receptor 2B4 (NK cell activation-inducing ligand) (NAIL) (NK celltype I CD244 2B4 370 receptor protein 2B4) (NKR2B4) (h2B4) (SLAM familymember 4) (SLAMF4) (Signaling lymphocytic activation molecule 4) (CDantigen CD244) Q5ZPR3 CD276_HUMAN CD276 antigen (4Ig-B7-H3) (B7 homolog3) (B7-H3) (Costimulatory molecule) (CD CD276 B7H3 534 antigen CD276)PSEC0249 UNQ309/PRO352 P34810 CD68_HUMAN Macrosialin (Gp110) (CD antigenCD68) CD68 354 P40259 CD79B_HUMAN B-cell antigen receptorcomplex-associated protein beta chain (B-cell-specific CD79B B29 IGB 229glycoprotein B29) (Ig-beta) (Immunoglobulin-associated B29 protein) (CDantigen CD79b) P01732 CD8A_HUMAN T-cell surface glycoprotein CD8 alphachain (T-lymphocyte differentiation antigen T8/Leu- CD8A MAL 235 2) (CDantigen CD8a) P06126 CD1A_HUMAN T-cell surface glycoprotein CD1a (T-cellsurface antigen T6/Leu-6) (hTa1 thymocyte CD1A 327 antigen) (CD antigenCD1a) P20273 CD22_HUMAN B-cell receptor CD22 (B-lymphocyte cell adhesionmolecule) (BL-CAM) (Sialic acid- CD22 SIGLEC2 847 binding Ig-like lectin2) (Siglec-2) (T-cell surface antigen Leu-14) (CD antigen CD22) P06127CD5_HUMAN T-cell surface glycoprotein CD5 (Lymphocyte antigen T1/Leu-1)(CD antigen CD5) CD5 LEU1 495 P10966 CD8B_HUMAN T-cell surfaceglycoprotein CD8 beta chain (CD antigen CD8b) CD8B CD8B1 210 P14209CD99_HUMAN CD99 antigen (12E7) (E2 antigen) (Protein MIC2) (T-cellsurface glycoprotein E2) (CD CD99 MIC2 MIC2X 185 antigen CD99) MIC2YP29017 CD1C_HUMAN T-cell surface glycoprotein CD1c (CD antigen CD1c)CD1C 333 P10747 CD28_HUMAN T-cell-specific surface glycoprotein CD28(TP44) (CD antigen CD28) CD28 220 A6NJW9 CD8BL_HUMAN Putative T-cellsurface glycoprotein CD8 beta-2 chain (CD8b pseudogene) CD8BP CD8B2 211Q9BYE9 CDHR2_HUMAN Cadherin-related family member 2 (Protocadherin LKC)(PC-LKC) (Protocadherin-24) CDHR2 PCDH24 PCLKC 1310 Q9HBB8 CDHR5_HUMANCadherin-related family member 5 (Mu-protocadherin) (Mucin andcadherin-like protein) CDHR5 MUCDHL MUPCDH 845 (Mucin-likeprotocadherin) (MLPCDH) UNQ2781/PRO7168 Q6UY09 CEA20_HUMANCarcinoembryonic antigen-related cell adhesion molecule 20 CEACAM20 585UNQ9366/PRO34155 Q3KPI0 CEA21_HUMAN Carcinoembryonic antigen-relatedcell adhesion molecule 21 CEACAM21 293 UNQ3098/PRO10075 P15391CD19_HUMAN B-lymphocyte antigen CD19 (B-lymphocyte surface antigen B4)(Differentiation antigen CD19 556 CD19) (T-cell surface antigen Leu-12)(CD antigen CD19) P15812 CD1E_HUMAN T-cell surface glycoprotein CD1e,membrane-associated (hCD1e) (R2G1) (CD antigen CD1E 388 CD1e) [Cleavedinto: T-cell surface glycoprotein CD1e, soluble (sCD1e)] Q15762CD226_HUMAN CD226 antigen (DNAX accessory molecule 1) (DNAM-1) (CDantigen CD226) CD226 DNAM1 336 P26842 CD27_HUMAN CD27 antigen (CD27Lreceptor) (T-cell activation antigen CD27) (T14) (Tumor necrosis CD27TNFRSF7 260 factor receptor superfamily member 7) (CD antigen CD27)P06729 CD2_HUMAN T-cell surface antigen CD2 (Erythrocyte receptor)(LFA-2) (LFA-3 receptor) (Rosette CD2 SRBC 351 receptor) (T-cell surfaceantigen T11/Leu-5) (CD antigen CD2) Q9NPF0 CD320_HUMAN CD320 antigen(8D6 antigen) (FDC-signaling molecule 8D6) (FDC-SM-8D6) CD320 8D6A 282(Transcobalamin receptor) (TCblR) (CD antigen CD320) UNQ198/PRO224P04234 CD3D_HUMAN T-cell surface glycoprotein CD3 delta chain (T-cellreceptor T3 delta chain) (CD antigen CD3D T3D 171 CD3d) P16070CD44_HUMAN CD44 antigen (CDw44) (Epican) (Extracellular matrix receptorIII) (ECMR-III) (GP90 CD44 LHR MDU2 742 lymphocyte homing/adhesionreceptor) (HUTCH-I) (Heparan sulfate proteoglycan) MDU3 MIC4 (Hermesantigen) (Hyaluronate receptor) (Phagocytic glycoprotein 1) (PGP-1)(Phagocytic glycoprotein I) (PGP-I) (CD antigen CD44) P30203 CD6_HUMANT-cell differentiation antigen CD6 (T12) (TP120) (CD antigen CD6)[Cleaved into: Soluble CD6 668 CD6] P33681 CD80_HUMAN T-lymphocyteactivation antigen CD80 (Activation B7-1 antigen) (BB1) (CTLA-4 counter-CD80 CD28LG 288 receptor B7.1) (B7) (CD antigen CD80) CD28LG1 LAB7P13688 CEAM1_HUMAN Carcinoembryonic antigen-related cell adhesionmolecule 1 (Biliary glycoprotein 1) (BGP- CEACAM1 BGP 526 1) (CD antigenCD66a) BGP1 P29016 CD1B_HUMAN T-cell surface glycoprotein CD1b (CDantigen CD1b) CD1B 333 Q9HCU0 CD248_HUMAN Endosialin (Tumor endothelialmarker 1) (CD antigen CD248) CD248 CD164L1 757 TEM1 P28906 CD34_HUMANHematopoietic progenitor cell antigen CD34 (CD antigen CD34) CD34 385P07766 CD3E_HUMAN T-cell surface glycoprotein CD3 epsilon chain (T-cellsurface antigen T3/Leu-4 epsilon CD3E T3E 207 chain) (CD antigen CD3e)P09693 CD3G_HUMAN T-cell surface glycoprotein CD3 gamma chain (T-cellreceptor T3 gamma chain) (CD CD3G T3G 182 antigen CD3g) Q6ZTQ4CDHR3_HUMAN Cadherin-related family member 3 (Cadherin-like protein 28)CDHR3 CDH28 885 P20963 CD3Z_HUMAN T-cell surface glycoprotein CD3 zetachain (T-cell receptor T3 zeta chain) (CD antigen CD247) CD247 CD3Z T3Z164 TCRZ P11912 CD79A_HUMAN B-cell antigen receptor complex-associatedprotein alpha chain (Ig-alpha) (MB-1 CD79A IGA MB1 226 membraneglycoprotein) (Membrane-bound immunoglobulin-associated protein)(Surface IgM-associated protein) (CD antigen CD79a) O75871 CEAM4_HUMANCarcinoembryonic antigen-related cell adhesion molecule 4(Carcinoembryonic antigen CEACAM4 CGM7 244 CGM7) (Non-specificcross-reacting antigen W236) Q13740 CD166_HUMAN CD166 antigen (Activatedleukocyte cell adhesion molecule) (CD antigen CD166) ALCAM MEMD 583Q99467 CD180_HUMAN CD180 antigen (Lymphocyte antigen 64)(Radioprotective 105 kDa protein) (CD antigen CD180) CD180 LY64 RP105661 Q8IX05 CD302_HUMAN CD302 antigen (C-type lectin BIMLEC) (C-typelectin domain family 13 member A) CD302 CLEC13A 232 (DEC205-associatedC-type lectin 1) (Type I transmembrane C-type lectin receptor DCL- DCL1KIAA0022 1) (CD antigen CD302) P20138 CD33_HUMAN Myeloid cell surfaceantigen CD33 (Sialic acid-binding Ig-like lectin 3) (Siglec-3) (gp67)CD33 SIGLEC3 364 (CD antigen CD33) P01730 CD4_HUMAN T-cell surfaceglycoprotein CD4 (T-cell surface antigen T4/Leu-3) (CD antigen CD4) CD4458 P09564 CD7_HUMAN T-cell antigen CD7 (GP40) (T-cell leukemia antigen)(T-cell surface antigen Leu-9) (TP41) CD7 240 (CD antigen CD7) Q01151CD83_HUMAN CD83 antigen (hCD83) (B-cell activation protein) (Cellsurface protein HB15) (CD antigen CD83 205 CD83) P42081 CD86_HUMANT-lymphocyte activation antigen CD86 (Activation B7-2 antigen) (B70)(BU63) (CTLA-4 CD86 CD28LG2 329 counter-receptor B7.2) (FUN-1) (CDantigen CD86) A6H8M9 CDHR4_HUMAN Cadherin-related family member 4(Cadherin-like protein 29) CDHR4 CDH29 788 UNQ9392/PRO34300 Q7Z692CEA19_HUMAN Carcinoembryonic antigen-related cell adhesion molecule 19(Carcinoembryonic antigen- like 1) CEACAM19 CEAL1 300 UNQ2973/PRO7436P40198 CEAM3_HUMAN Carcinoembryonic antigen-related cell adhesionmolecule 3 (Carcinoembryonic antigenCGM1) (CD antigen CD66d) CEACAM3CD66D CGM1 252 Q9H9P2 CHODL_HUMAN Chondrolectin (Transmembrane proteinMT75) CHODL C21orf68 273 PRED12 UNQ872/PRO1890 Q08708 CLM6_HUMANCMRF35-like molecule 6 (CLM-6) (CD300 antigen-like family member C)(CMRF35-A1) CD300C CMRF35 CMRF35A 224 (CMRF-35) (Immunoglobulinsuperfamily member 16) (IgSF16) (CD antigen CD300c) CMRF35A1 IGSF16O14967 CLGN_HUMAN Calmegin CLGN 610 Q496F6 CLM2_HUMAN CMRF35-likemolecule 2 (CLM-2) (CD300 antigen-like family member E) (CMRF35-A5)CD300E CD300LE 205 (Immune receptor expressed on myeloid cells 2)(IREM-2) (Polymeric immunoglobulin CLM2 CMRF35A5 receptor 2) (PIgR-2)(PIgR2) (Poly-Ig receptor 2) (CD antigen CD300e) IREM2 Q6UXG3 CLM9_HUMANCMRF35-like molecule 9 (CLM-9) (CD300 antigen-like family member G)(Triggering CD300LG CLM9 TREM4 332 receptor expressed on myeloid cells4) (TREM-4) (CD antigen CD300g) UNQ422/PRO846 Q9UQC9 CLCA2_HUMANCalcium-activated chloride channel regulator 2 (EC 3.4.—.—)(Calcium-activated chloride CLCA2 CACC3 943 channel family member 2)(hCLCA2) (Calcium-activated chloride channel protein 3) (CaCC-3)(hCaCC-3) [Cleaved into: Calcium-activated chloride channel regulator 2,109 kDa form; Calcium-activated chloride channel regulator 2, 35 kDaform] Q9H6B4 CLMP_HUMAN CXADR-like membrane protein (Adipocyte adhesionmolecule) (Coxsackie- and CLMP ACAM ASAM 373 adenovirus receptor-likemembrane protein) (CAR-like membrane protein) UNQ318/PRO363 Q96F05CK024_HUMAN Uncharacterized protein C11orf24 (Protein DM4E3) C11orf24FP2568 449 UNQ1872/PRO4315 Q6NUJ2 CK087_HUMAN Uncharacterized proteinC11orf87 C11orf87 197 A8K4G0 CLM7_HUMAN CMRF35-like molecule 7 (CLM-7)(CD300 antigen-like family member B) (CMRF35-A2) CD300LB CD300B 201(Immune receptor expressed on myeloid cells 3) (IREM-3) (Leukocytemono-Ig-like CLM7 CMRF35A2 receptor 5) (Triggering receptor expressed onmyeloid cells 5) (TREM-5) (CD antigen IREM3 LMIR5 CD300b) TREM5UNQ2530/PRO6029 Q9UGN4 CLM8_HUMAN CMRF35-like molecule 8 (CLM-8) (CD300antigen-like family member A) (CMRF-35-H9) CD300A CMRF35H 299(CMRF35-H9) (CMRF35-H) (IRC1/IRC2) (Immunoglobulin superfamily member12) IGSF12 HSPC083 (IgSF12) (Inhibitory receptor protein 60) (IRp60) (NKinhibitory receptor) (CD antigen CD300a) Q96NU0 CNT3B_HUMANContactin-associated protein-like 3B (Cell recognition molecule Caspr3b)CNTNAP3B 1288 CASPR3B P78357 CNTP1_HUMAN Contactin-associated protein 1(Caspr) (Caspr1) (Neurexin IV) (Neurexin-4) (p190) CNTNAP1 CASPR 1384NRXN4 Q9UHC6 CNTP2_HUMAN Contactin-associated protein-like 2 (Cellrecognition molecule Caspr2) CNTNAP2 CASPR2 1331 KIAA0868 Q9C0A0CNTP4_HUMAN Contactin-associated protein-like 4 (Cell recognitionmolecule Caspr4) CNTNAP4 CASPR4 1308 KIAA1763 Q8WYK1 CNTP5_HUMANContactin-associated protein-like 5 (Cell recognition molecule Caspr5)CNTNAP5 CASPR5 1306 Q8TDQ1 CLM1_HUMAN CMRF35-like molecule 1 (CLM-1)(CD300 antigen-like family member F) (Immune CD300LF CD300F 290 receptorexpressed on myeloid cells 1) (IREM-1) (Immunoglobulin superfamilymember CLM1 IGSF13 13) (IgSF13) (NK inhibitory receptor) (CD antigenCD300f) IREM1 NKIR UNQ3105/PRO10111 Q5T292 CJ128_HUMAN Putativeuncharacterized protein C10orf128 C10orf128 105 Q86T13 CLC14_HUMANC-type lectin domain family 14 member A (Epidermal growth factorreceptor 5) (EGFR-5) CLEC14A C14orf27 490 EGFR5 UNQ236/PRO269 Q6UXZ3CLM4_HUMAN CMRF35-like molecule 4 (CLM-4) (CD300 antigen-like familymember D) (CMRF35-A4) CD300LD CD300D 194 (CD antigen CD300d) CMRF35A4UNQ9218/PRO28686 Q9BZ76 CNTP3_HUMAN Contactin-associated protein-like 3(Cell recognition molecule Caspr3) CNTNAP3 CASPR3 1288 KIAA1714 Q86TY3CN037_HUMAN Uncharacterized protein C14orf37 C14orf37 774 Q9HC73CRLF2_HUMAN Cytokine receptor-like factor 2 (Cytokine receptor-like 2)(IL-XR) (Thymic stromal CRLF2 CRL2 ILXR TSLPR 371 lymphopoietin proteinreceptor) (TSLP receptor) Q9BVV8 CS024_HUMAN Uncharacterized membraneprotein C19orf24 C19orf24 132 P09603 CSF1_HUMAN Macrophagecolony-stimulating factor 1 (CSF-1) (M-CSF) (MCSF) (Lanimostim) [CleavedCSF1 554 into: Processed macrophage colony-stimulating factor 1] Q5IJ48CRUM2_HUMAN Protein crumbs homolog 2 (Crumbs-like protein 2) CRB2 1285Q96PZ7 CSMD1_HUMAN CUB and sushi domain-containing protein 1 (CUB andsushi multiple domains protein 1) CSMD1 KIAA1890 3565 UNQ5952/PRO19863O95196 CSPG5_HUMAN Chondroitin sulfate proteoglycan 5 (Acidicleucine-rich EGF-like domain-containing brain CSPG5 CALEB 566 protein)(Neuroglycan C) NGC Q9BUF7 CRUM3_HUMAN Protein crumbs homolog 3 CRB3 120UNQ588/PRO1158 O94985 CSTN1_HUMAN Calsyntenin-1 (Alcadein-alpha)(Alc-alpha) (Alzheimer-related cadherin-like protein) (Non- CLSTN1 CS1981 classical cadherin XB31alpha) [Cleaved into: Soluble Alc-alpha(SAlc-alpha); CTF1-alpha KIAA0911 (C-terminal fragment 1-alpha)] Q6ZRH7CTSRG_HUMAN Cation channel sperm-associated protein subunit gammaCATSPERG 1159 C19orf15 Q86UP6 CUZD1_HUMAN CUB and zona pellucida-likedomain-containing protein 1 (CUB and ZP domain- CUZD1 607 containingprotein 1) (Transmembrane protein UO-44) UNQ224/PRO257 Q5JRM2CX066_HUMAN Uncharacterized protein CXorf66 CXorf66 361 Q8NEA5CS018_HUMAN Uncharacterized protein C19orf18 C19orf18 215 P17927CR1_HUMAN Complement receptor type 1 (C3b/C4b receptor) (CD antigenCD35) CR1 C3BR 2039 P20023 CR2_HUMAN Complement receptor type 2 (Cr2)(Complement C3d receptor) (Epstein-Barr virus CR2 C3DR 1033 receptor)(EBV receptor) (CD antigen CD21) P15509 CSF2R_HUMANGranulocyte-macrophage colony-stimulating factor receptor subunit alpha(GM-CSF-R- CSF2RA CSF2R 400 alpha) (GMCSFR-alpha) (GMR-alpha) (CDw116)(CD antigen CD116) CSF2RY Q99062 CSF3R_HUMAN Granulocytecolony-stimulating factor receptor (G-CSF receptor) (G-CSF-R) (CDantigen CSF3R GCSFR 836 CD114) Q9BQT9 CSTN3_HUMAN Calsyntenin-3(Alcadein-beta) (Alc-beta) CLSTN3 CS3 956 KIAA0726 Q9NZV1 CRIM1_HUMANCysteine-rich motor neuron 1 protein (CRIM-1) (Cysteine-richrepeat-containing protein CRIM1 S52 1036 S52) [Cleaved into: Processedcysteine-rich motor neuron 1 protein] UNQ1886/PRO4330 P82279 CRUM1_HUMANProtein crumbs homolog 1 CRB1 1406 Q6UVK1 CSPG4_HUMAN Chondroitinsulfate proteoglycan 4 (Chondroitin sulfate proteoglycan NG2) (MelanomaCSPG4 MCSP 2322 chondroitin sulfate proteoglycan) (Melanoma-associatedChondroitin sulfate proteoglycan) P16410 CTLA4_HUMAN CytotoxicT-lymphocyte protein 4 (Cytotoxic T-lymphocyte-associated antigen 4)(CTLA- CTLA4 CD152 223 4) (CD antigen CD152) Q86XM0 CTSRD_HUMAN Cationchannel sperm-associated protein subunit delta (CatSper-delta)(CatSperdelta) CATSPERD TMEM146 798 (Transmembrane protein 146) P78310CXAR_HUMAN Coxsackievirus and adenovirus receptor (CAR) (hCAR)(CVB3-binding protein) CXADR CAR 365 (Coxsackievirus B-adenovirusreceptor) (HCVADR) O95727 CRTAM_HUMAN Cytotoxic and regulatory T-cellmolecule (Class-I MHC-restricted T-cell-associated CRTAM 393 molecule)(CD antigen CD355) P07333 CSF1R_HUMAN Macrophage colony-stimulatingfactor 1 receptor (CSF-1 receptor) (CSF-1-R) (CSF-1R) CSF1R FMS 972(M-CSF-R) (EC 2.7.10.1) (Proto-oncogene c-Fms) (CD antigen CD115) Q4G0I0CSMT1_HUMAN Protein CCSMST1 CCSMST1 132 C16orf91 Q9H4D0 CSTN2_HUMANCalsyntenin-2 (Alcadein-gamma) (Alc-gamma) CLSTN2 CS2 955 Q9H2A7CXL16_HUMAN C-X-C motif chemokine 16 (Scavenger receptor forphosphatidylserine and oxidized low CXCL16 SCYB16 SRPSOX 254 densitylipoprotein) (SR-PSOX) (Small-inducible cytokine B16) (TransmembraneUNQ2759/PRO6714 chemokine CXCL16) P08174 DAF_HUMAN Complementdecay-accelerating factor (CD antigen CD55) CD55 CR DAF 381 Q14118DAG1_HUMAN Dystroglycan (Dystrophin-associated glycoprotein 1) [Cleavedinto: Alpha-dystroglycan DAG1 895 (Alpha-DG); Beta-dystroglycan(Beta-DG)] Q96J86 CYYR1_HUMAN Cysteine and tyrosine-rich protein 1(Proline-rich domain-containing protein) CYYR1 C21orf95 154 P43146DCC_HUMAN Netrin receptor DCC (Colorectal cancer suppressor)(Immunoglobulin superfamily DCC DCC IGDCC1 1447 subclass member 1)(Tumor suppressor protein DCC) Q08345 DDR1_HUMAN Epithelial discoidindomain-containing receptor 1 (Epithelial discoidin domain receptor 1)DDR1 CAK EDDR1 913 (EC 2.7.10.1) (CD167 antigen-like family member A)(Cell adhesion kinase) (Discoidin NEP NTRK4 PTK3A receptor tyrosinekinase) (HGK2) (Mammary carcinoma kinase 10) (MCK-10) (Protein- RTK6TRKE tyrosine kinase 3A) (Protein-tyrosine kinase RTK-6) (TRK E)(Tyrosine kinase DDR) (Tyrosine-protein kinase CAK) (CD antigen CD167a)Q16832 DDR2_HUMAN Discoidin domain-containing receptor 2 (Discoidindomain receptor 2) (EC 2.7.10.1) DDR2 NTRKR3 855 (CD167 antigen-likefamily member B) (Discoidin domain-containing receptor tyrosine TKTTYRO10 kinase 2) (Neurotrophic tyrosine kinase, receptor-related 3)(Receptor protein-tyrosine kinase TKT) (Tyrosine-protein kinase TYRO10)(CD antigen CD167b) Q8N8Z6 DCBD1_HUMAN Discoidin, CUB and LCCLdomain-containing protein 1 DCBLD1 715 Q96PD2 DCBD2_HUMAN Discoidin, CUBand LCCL domain-containing protein 2 (CUB, LCCL and coagulation DCBLD2CLCP1 775 factor V/VIII-homology domains protein 1) (Endothelial andsmooth muscle cell-derived ESDN neuropilin-like protein) P28068DMB_HUMAN HLA class II histocompatibility antigen, DM beta chain (MHCclass II antigen DMB) HLA-DMB DMB 263 (Really interesting new gene 7protein) RING7 P80370 DLK1_HUMAN Protein delta homolog 1 (DLK-1) (pG2)[Cleaved into: Fetal antigen 1 (FA1)] DLK1 DLK 383 Q9NYJ7 DLL3_HUMANDelta-like protein 3 (Drosophila Delta homolog 3) (Delta3) DLL3 618P28067 DMA_HUMAN HLA class II histocompatibility antigen, DM alpha chain(MHC class II antigen DMA) HLA-DMA DMA 261 (Really interesting new gene6 protein) RING6 P06340 DOA_HUMAN HLA class II histocompatibilityantigen, DO alpha chain (MHC DN-alpha) (MHC DZ alpha) HLA-DOA HLA-DNA250 (MHC class II antigen DOA) HLA-DZA Q6UY11 DLK2_HUMAN Protein deltahomolog 2 (DLK-2) (Epidermal growth factor-like protein 9) (EGF-likeprotein DLK2 EGFL9 383 9) UNQ2903/PRO28633 Q8NFT8 DNER_HUMAN Delta andNotch-like epidermal growth factor-related receptor DNER BET 737UNQ262/PRO299 P20036 DPA1_HUMAN HLA class II histocompatibility antigen,DP alpha 1 chain (DP(W3)) (DP(W4)) (HLA-SB HLA-DPA1 HLA- 260 alphachain) (MHC class II DP3-alpha) (MHC class II DPA1) DP1A HLASB P79483DRB3_HUMAN HLA class II histocompatibility antigen, DR beta 3 chain (MHCclass II antigen DRB3) HLA-DRB3 266 Q96KC8 DNJC1_HUMAN DnaJ homologsubfamily C member 1 (DnaJ protein homolog MTJ1) DNAJC1 HTJ1 554 Q8TD84DSCL1_HUMAN Down syndrome cell adhesion molecule-like protein 1 (Downsyndrome cell adhesion DSCAML1 2053 molecule 2) DSCAM2 KIAA1132 O00548DLL1_HUMAN Delta-like protein 1 (Drosophila Delta homolog 1) (Delta1)(H-Delta-1) DLL1 723 UNQ146/PRO172 Q02487 DSC2_HUMAN Desmocollin-2(Cadherin family member 2) (Desmocollin-3) (Desmosomal glycoprotein II)DSC2 CDHF2 DSC3 901 (Desmosomal glycoprotein III) O60469 DSCAM_HUMANDown syndrome cell adhesion molecule (CHD2) DSCAM 2012 Q9NR61 DLL4_HUMANDelta-like protein 4 (Drosophila Delta homolog 4) (Delta4) DLL4 685UNQ1895/PRO4341 P13765 DOB_HUMAN HLA class II histocompatibilityantigen, DO beta chain (MHC class II antigen DOB) HLA-DOB 273 P01906DQA2_HUMAN HLA class II histocompatibility antigen, DQ alpha 2 chain (DXalpha chain) (HLA class II HLA-DQA2 HLA-DXA 255 histocompatibilityantigen, DQ(6) alpha chain) (HLA-DQA1) (MHC class II DQA2) P01920DQB1_HUMAN HLA class II histocompatibility antigen, DQ beta 1 chain (MHCclass II antigen DQB1) HLA-DQB1 HLA-DQB 261 Q30154 DRB5_HUMAN HLA classII histocompatibility antigen, DR beta 5 chain (DR beta-5) (DR2-beta-2)(Dw2) HLA-DRB5 266 (MHC class II antigen DRB5) Q14574 DSC3_HUMANDesmocollin-3 (Cadherin family member 3) (Desmocollin-4) (HT-CP) DSC3CDHF3 DSC4 896 P01909 DQA1_HUMAN HLA class II histocompatibilityantigen, DQ alpha 1 chain (DC-1 alpha chain) (DC-alpha) HLA-DQA1 254(HLA-DCA) (MHC class II DQA1) P32926 DSG3_HUMAN Desmoglein-3 (130 kDapemphigus vulgaris antigen) (PVA) (Cadherin family member 6) DSG3 CDHF6999 Q9NZJ5 E2AK3_HUMAN Eukaryotic translation initiation factor 2-alphakinase 3 (EC 2.7.11.1) (PRKR-like EIF2AK3 PEK PERK 1116 endoplasmicreticulum kinase) (Pancreatic eIF2-alpha kinase) (HsPEK) P04440DPB1_HUMAN HLA class II histocompatibility antigen, DP beta 1 chain (HLAclass II histocompatibility HLA-DPB1 HLA-DP1B 258 antigen, DP(W4) betachain) (MHC class II antigen DPB1) P13762 DRB4_HUMAN HLA class IIhistocompatibility antigen, DR beta 4 chain (MHC class II antigen DRB4)HLA-DRB4 266 Q86SJ6 DSG4_HUMAN Desmoglein-4 (Cadherin family member 13)DSG4 CDHF13 1040 Q3MIW9 DPCR1_HUMAN Diffuse panbronchiolitis criticalregion protein 1 DPCR1 C6orf37 PBLT 517 P01903 DRA_HUMAN HLA class IIhistocompatibility antigen, DR alpha chain (MHC class II antigen DRA)HLA-DRA HLA-DRA1 254 Q08554 DSC1_HUMAN Desmocollin-1 (Cadherin familymember 1) (Desmosomal glycoprotein 2/3) (DG2/DG3) DSC1 CDHF1 894 Q02413DSG1_HUMAN Desmoglein-1 (Cadherin family member 4) (Desmosomalglycoprotein 1) (DG1) (DGI) DSG1 CDHF4 1049 (Pemphigus foliaceusantigen) P05538 DQB2_HUMAN HLA class II histocompatibility antigen, DQbeta 2 chain (HLA class II histocompatibility HLA-DQB2 HLA-DXB 268antigen, DX beta chain) (MHC class II antigen DQB2) Q14126 DSG2_HUMANDesmoglein-2 (Cadherin family member 5) (HDGC) DSG2 CDHF5 1118 P01133EGF_HUMAN Pro-epidermal growth factor (EGF) [Cleaved into: Epidermalgrowth factor (Urogastrone)] EGF 1207 Q19T08 ECSCR_HUMAN Endothelialcell-specific chemotaxis regulator (Apoptosis regulator throughmodulating ECSCR ECSM2 205 IAP expression) (ARIA) (Endothelialcell-specific molecule 2) Q9UNE0 EDAR_HUMAN Tumor necrosis factorreceptor superfamily member EDAR (Anhidrotic ectodysplasin EDAR DL 448receptor 1) (Downless homolog) (EDA-A1 receptor) (Ectodermal dysplasiareceptor) (Ectodysplasin-A receptor) P98172 EFNB1_HUMAN Ephrin-B1(EFL-3) (ELK ligand) (ELK-L) (EPH-related receptor tyrosine kinaseligand 2) EFNB1 EFL3 346 (LERK-2) EPLG2 LERK2 Q15768 EFNB3_HUMANEphrin-B3 (EPH-related receptor transmembrane ligand ELK-L3)(EPH-related receptor EFNB3 EPLG8 340 tyrosine kinase ligand 8) (LERK-8)LERK8 Q9NPA0 EMC7_HUMAN ER membrane protein complex subunit 7 EMC7C11orf3 242 C15orf24 HT022 UNQ905/PRO1926 Q902F9 EN113_HUMAN Endogenousretrovirus group K member 113 Env polyprotein (EnvK5 protein) (EnvelopeHERVK_113 699 polyprotein) (HERV-K113 envelope protein) (HERV-K_19p13.11provirus ancestral Env polyprotein) [Cleaved into: Surface protein (SU);Transmembrane protein (TM)] Q6UWV6 ENPP7_HUMAN Ectonucleotidepyrophosphatase/phosphodiesterase family member 7 (E-NPP 7) (NPP-7)ENPP7 458 (EC 3.1.4.12) (Alkaline sphingomyelin phosphodiesterase)(Intestinal alkaline UNQ3077/PRO9912 sphingomyelinase) (Alk-SMase)P61566 ENK24_HUMAN Endogenous retrovirus group K member 24 Envpolyprotein (Envelope polyprotein) ERVK-24 588 (HERV-K101 envelopeprotein) (HERV-K_22q11.21 provirus ancestral Env polyprotein) [Cleavedinto: Surface protein (SU); Transmembrane protein (TM)] Q902F8ENK8_HUMAN Endogenous retrovirus group K member 8 Env polyprotein (EnvK6protein) (Envelope ERVK-8 699 polyprotein) (HERV-K115 envelope protein)(HERV-K_8p23.1 provirus ancestral Env polyprotein) [Cleaved into:Surface protein (SU); Transmembrane protein (TM)] P29320 EPHA3_HUMANEphrin type-A receptor 3 (EC 2.7.10.1) (EPH-like kinase 4) (EK4) (hEK4)(HEK) (Human EPHA3 ETK ETK1 983 embryo kinase) (Tyrosine-protein kinaseTYRO4) (Tyrosine-protein kinase receptor HEK TYRO4 ETK1) (Eph-liketyrosine kinase 1) P54764 EPHA4_HUMAN Ephrin type-A receptor 4 (EC2.7.10.1) (EPH-like kinase 8) (EK8) (hEK8) (Tyrosine- EPHA4 HEK8 SEK 986protein kinase TYRO1) (Tyrosine-protein kinase receptor SEK) TYRO1Q9UF33 EPHA6_HUMAN Ephrin type-A receptor 6 (EC 2.7.10.1) (EPH homologykinase 2) (EHK-2) (EPH-like EPHA6 EHK2 1036 kinase 12) (EK12) HEK12Q5JZY3 EPHAA_HUMAN Ephrin type-A receptor 10 (EC 2.7.10.1) EPHA10 1008P19235 EPOR_HUMAN Erythropoietin receptor (EPO-R) EPOR 508 P04626ERBB2_HUMAN Receptor tyrosine-protein kinase erbB-2 (EC 2.7.10.1)(Metastatic lymph node gene 19 ERBB2 HER2 1255 protein) (MLN 19)(Proto-oncogene Neu) (Proto-oncogene c-ErbB-2) (Tyrosine kinase- MLN19NEU NGL type cell surface receptor HER2) (p185erbB2) (CD antigen CD340)P52799 EFNB2_HUMAN Ephrin-B2 (EPH-related receptor tyrosine kinaseligand 5) (LERK-5) (HTK ligand) (HTK-L) EFNB2 EPLG5 333 HTKL LERK5P17813 EGLN_HUMAN Endoglin (CD antigen CD105) ENG END 658 Q5UCC4EMC10_HUMAN ER membrane protein complex subunit 10 (Hematopoietic signalpeptide-containing EMC10 C19orf63 262 membrane domain-containingprotein 1) HSM1 INM02 UNQ764/PRO1556 Q69384 ENK6_HUMAN Endogenousretrovirus group K member 6 Env polyprotein (EnvK2 protein) (EnvelopeERVK-6 ERVK6 699 polyprotein) (HERV-K(C7) envelope protein)(HERV-K(HML-2.HOM) envelope protein) (HERV-K108 envelope protein)(HERV-K_7p22.1 provirus ancestral Env polyprotein) [Cleaved into:Surface protein (SU); Transmembrane protein (TM)] Q9UKH3 ENK9_HUMANEndogenous retrovirus group K member 9 Env polyprotein (EnvK4 protein)(Envelope ERVK-9 698 polyprotein) (HERV-K(C6) envelope protein)(HERV-K109 envelope protein) (HERV- K_6q14.1 provirus ancestral Envpolyprotein) [Cleaved into: Surface protein (SU); Transmembrane protein(TM)] Q6UW88 EPGN_HUMAN Epigen (Epithelial mitogen) (EPG) EPGN 154UNQ3072/PRO9904 P29317 EPHA2_HUMAN Ephrin type-A receptor 2 (EC2.7.10.1) (Epithelial cell kinase) (Tyrosine-protein kinase EPHA2 ECK976 receptor ECK) P54753 EPHB3_HUMAN Ephrin type-B receptor 3 (EC2.7.10.1) (EPH-like tyrosine kinase 2) (EPH-like kinase 2) EPHB3 ETK2HEK2 998 (Embryonic kinase 2) (EK2) (hEK2) (Tyrosine-protein kinaseTYRO6) TYRO6 O15197 EPHB6_HUMAN Ephrin type-B receptor 6 (HEP)(Tyrosine-protein kinase-defective receptor EPH-6) EPHB6 1021 O14944EREG_HUMAN Proepiregulin [Cleaved into: Epiregulin (EPR)] EREG 169B6SEH8 ERVV1_HUMAN Endogenous retrovirus group V member 1 Envpolyprotein (HERV-V_19q13.41 provirus ERVV-1 ENVV1 477 ancestral Envpolyprotein 1) P00533 EGFR_HUMAN Epidermal growth factor receptor (EC2.7.10.1) (Proto-oncogene c-ErbB-1) (Receptor EGFR ERBB 1210tyrosine-protein kinase erbB-1) ERBB1 HER1 Q8N766 EMC1_HUMAN ER membraneprotein complex subunit 1 EMC1 KIAA0090 993 PSEC0263 O42043 ENK18_HUMANEndogenous retrovirus group K member 18 Env polyprotein (Envelopepolyprotein) ERVK-18 560 (HERV-K(C1a) envelope protein) (HERV-K110envelope protein) (HERV-K18 envelope protein) (HERV-K18 superantigen)(HERV-K_1q23.3 provirus ancestral Env polyprotein) (IDDMK1, 2 22envelope protein) (IDDMK1, 2 22 superantigen) [Cleaved into: Surfaceprotein (SU); Transmembrane protein (TM)] O71037 ENK19_HUMAN Endogenousretrovirus group K member 19 Env polyprotein (EnvK3 protein) (EnvelopeERVK-19 699 polyprotein) (HERV-K(C19) envelope protein) (HERV-K_19q11provirus ancestral Env polyprotein) [Cleaved into: Surface protein (SU);Transmembrane protein (TM)] Q15375 EPHA7_HUMAN Ephrin type-A receptor 7(EC 2.7.10.1) (EPH homology kinase 3) (EHK-3) (EPH-like EPHA7 EHK3 998kinase 11) (EK11) (hEK11) HEK11 Q9NQ60 EQTN_HUMAN Equatorin (Acrosomeformation-associated factor) EQTN AFAF 294 C9orf11 P61565 ENK21_HUMANEndogenous retrovirus group K member 21 Env polyprotein (EnvK1 protein)(Envelope ERVK-21 698 polyprotein) (HERV-K_12q14.1 provirus ancestralEnv polyprotein) [Cleaved into: Surface protein (SU); Transmembraneprotein (TM)] Q9UNN8 EPCR_HUMAN Endothelial protein C receptor(Activated protein C receptor) (APC receptor) (Endothelial PROCR EPCR238 cell protein C receptor) (CD antigen CD201) P54762 EPHB1_HUMANEphrin type-B receptor 1 (EC 2.7.10.1) (ELK) (EPH tyrosine kinase 2)(EPH-like kinase 6) EPHB1 ELK EPHT2 984 (EK6) (hEK6)(Neuronally-expressed EPH-related tyrosine kinase) (NET) (Tyrosine- HEK6NET protein kinase receptor EPH-2) P54760 EPHB4_HUMAN Ephrin type-Breceptor 4 (EC 2.7.10.1) (Hepatoma transmembrane kinase) (Tyrosine-EPHB4 HTK MYK1 987 protein kinase TYRO11) TYRO11 P21860 ERBB3_HUMANReceptor tyrosine-protein kinase erbB-3 (EC 2.7.10.1)(Proto-oncogene-like protein c- ERBB3 HER3 1342 ErbB-3) (Tyrosinekinase-type cell surface receptor HER3) A8MVW0 F1712_HUMAN ProteinFAM171A2 FAM171A2 826 Q5JX69 F209B_HUMAN Protein FAM209B FAM209B 171C20orf107 P0C7U0 ELFN1_HUMAN Protein ELFN1 (Extracellular leucine-richrepeat and fibronectin type-III domain- ELFN1 PPP1R28 828 containingprotein 1) (Protein phosphatase 1 regulatory subunit 28) Q6PCB8EMB_HUMAN Embigin EMB 327 Q9Y6X5 ENPP4_HUMANBis(5′-adenosyl)-triphosphatase ENPP4 (EC 3.6.1.29) (AP3A hydrolase)(AP3Aase) ENPP4 KIAA0879 453 (Ectonucleotidepyrophosphatase/phosphodiesterase family member 4) (E-NPP 4) (NPP- NPP44) P21709 EPHA1_HUMAN Ephrin type-A receptor 1 (hEpha1) (EC 2.7.10.1)(EPH tyrosine kinase) (EPH tyrosine EPHA1 EPH EPHT 976 kinase 1)(Erythropoietin-producing hepatoma receptor) (Tyrosine-protein kinasereceptor EPHT1 EPH) P54756 EPHA5_HUMAN Ephrin type-A receptor 5 (EC2.7.10.1) (Brain-specific kinase) (EPH homology kinase 1) EPHA5 BSK EHK11037 (EHK-1) (EPH-like kinase 7) (EK7) (hEK7) HEK7 TYRO4 P29322EPHA8_HUMAN Ephrin type-A receptor 8 (EC 2.7.10.1) (EPH- and ELK-relatedkinase) (EPH-like kinase EPHA8 EEK HEK3 1005 3) (EK3) (hEK3)(Tyrosine-protein kinase receptor EEK) KIAA1459 P29323 EPHB2_HUMANEphrin type-B receptor 2 (EC 2.7.10.1) (Developmentally-regulatedEph-related tyrosine EPHB2 DRT EPHT3 1055 kinase) (ELK-related tyrosinekinase) (EPH tyrosine kinase 3) (EPH-like kinase 5) (EK5) EPTH3 ERK HEK5(hEK5) (Renal carcinoma antigen NY-REN-47) (Tyrosine-protein kinaseTYRO5) TYRO5 (Tyrosine-protein kinase receptor EPH-3) P03372 ESR1_HUMANEstrogen receptor (ER) (ER-alpha) (Estradiol receptor) (Nuclear receptorsubfamily 3 ESR1 ESR NR3A1 595 group A member 1) Q15884 F1892_HUMANProtein FAM189A2 (Protein X123) FAM189A2 C9orf61 450 X123 P16422EPCAM_HUMAN Epithelial cell adhesion molecule (Ep-CAM)(Adenocarcinoma-associated antigen) (Cell EPCAM GA733-2 314 surfaceglycoprotein Trop-1) (Epithelial cell surface antigen) (Epithelialglycoprotein) M1S2 M4S1 MIC18 (EGP) (Epithelial glycoprotein 314)(EGP314) (hEGP314) (KS 1/4 antigen) (KSA) (Major TACSTD1 TROP1gastrointestinal tumor-associated protein GA733-2) (Tumor-associatedcalcium signal transducer 1) (CD antigen CD326) Q15303 ERBB4_HUMANReceptor tyrosine-protein kinase erbB-4 (EC 2.7.10.1)(Proto-oncogene-like protein c- ERBB4 HER4 1308 ErbB-4) (Tyrosinekinase-type cell surface receptor HER4) (p180erbB4) [Cleaved into: ERBB4intracellular domain (4ICD) (E4ICD) (s80HER4)] O75460 ERN1_HUMANSerine/threonine-protein kinase/endoribonuclease IRE1 (Endoplasmicreticulum-to- ERN1 IRE1 977 nucleus signaling 1) (Inositol-requiringprotein 1) (hIRE1p) (Ire1-alpha) (IRE1a) [Includes:Serine/threonine-protein kinase (EC 2.7.11.1); Endoribonuclease (EC3.1.26.—)] P58658 EVA1C_HUMAN Protein eva-1 homolog C (Protein FAM176C)(SUE21) EVA1C C21orf63 441 C21orf64 FAM176C PRED34 UNQ2504/PRO5993P22794 EVI2A_HUMAN Protein EVI2A (Ecotropic viral integration site 2Aprotein homolog) (EVI-2A) EVI2A EVDA EVI2 236 Q5VUB5 F1711_HUMAN ProteinFAM171A1 (Astroprincin) FAM171A1 890 C10orf38 Q6V0I7 FAT4_HUMANProtocadherin Fat 4 (hFat4) (Cadherin family member 14) (FAT tumorsuppressor FAT4 CDHF14 4981 homolog 4) (Fat-like cadherin protein FAT-J)FATJ Nbla00548 Q96PL5 ERMAP_HUMAN Erythroid membrane-associated protein(hERMAP) (Radin blood group antigen) (Scianna ERMAP RD SC 475 bloodgroup antigen) Q76MJ5 ERN2_HUMAN Serine/threonine-proteinkinase/endoribonuclease IRE2 (Endoplasmic reticulum-to- ERN2 IRE2 926nucleus signaling 2) (Inositol-requiring protein 2) (hIRE2p) (Ire1-beta)(IRE1b) [Includes: Serine/threonine-protein kinase (EC 2.7.11.1);Endoribonuclease (EC 3.1.26.—)] Q96AP7 ESAM_HUMAN Endothelialcell-selective adhesion molecule ESAM 390 UNQ220/PRO246 P34910EVI2B_HUMAN Protein EVI2B (Ecotropic viral integration site 2B proteinhomolog) (EVI-2B) (CD antigen EVI2B EVDB 448 CD361) Q3ZCQ3 F174B_HUMANMembrane protein FAM174B FAM174B 159 Q8WWV6 FCAMR_HUMAN High affinityimmunoglobulin alpha and immunoglobulin mu Fc receptor (Fc alpha/muFCAMR FKSG87 532 receptor) (CD antigen CD351) P30273 FCERG_HUMAN Highaffinity immunoglobulin epsilon receptor subunit gamma (Fc receptorgamma-chain) FCER1G 86 (FcRgamma) (Fc-epsilon RI-gamma) (IgE Fc receptorsubunit gamma) (FceRI gamma) Q8TBP5 F174A_HUMAN Membrane protein FAM174A(Hepatitis C virus NS5A-transactivated protein 6) (HCV FAM174A NS5ATP6TMEM157 190 NS5A-transactivated protein 6) (Transmembrane protein 157)UNQ1912/PRO4371 P31995 FCG2C_HUMAN Low affinity immunoglobulin gamma Fcregion receptor II-c (IgG Fc receptor II-c) FCGR2C CD32 323 (CDw32)(Fc-gamma RII-c) (Fc-gamma-RIIc) (FcRII-c) (CD antigen CD32) FCG2 IGFR2P55899 FCGRN_HUMAN IgG receptor FcRn large subunit p51 (FcRn) (IgG Fcfragment receptor transporter alpha FCGRT FCRN 365 chain) (Neonatal Fcreceptor) Q96LA5 FCRL2_HUMAN Fc receptor-like protein 2 (FcR-likeprotein 2) (FcRL2) (Fc receptor homolog 2) (FcRH2) FCRL2 FCRH2 508 (IFGPfamily protein 4) (Immunoglobulin receptor translocation-associatedprotein 4) IFGP4 IRTA4 (SH2 domain-containing phosphatase anchorprotein 1) (CD antigen CD307b) SPAP1 UNQ9236/PRO31998 Q96RD9 FCRL5_HUMANFc receptor-like protein 5 (FcR-like protein 5) (FcRL5) (BXMAS1) (Fcreceptor homolog 5) FCRL5 FCRH5 IRTA2 977 (FcRH5) (Immune receptortranslocation-associated protein 2) (CD antigen CD307e) UNQ503/PRO820P31994 FCG2B_HUMAN Low affinity immunoglobulin gamma Fc region receptorII-b (IgG Fc receptor II-b) FCGR2B CD32 310 (CDw32) (Fc-gamma RII-b)(Fc-gamma-RIIb) (FcRII-b) (CD antigen CD32) FCG2 IGFR2 Q96PJ5FCRL4_HUMAN Fc receptor-like protein 4 (FcR-like protein 4) (FcRL4) (Fcreceptor homolog 4) (FcRH4) FCRL4 FCRH4 515 (IFGP family protein 2)(hIFGP2) (Immune receptor translocation-associated protein 1) IFGP2IRTA1 (CD antigen CD307d) P22607 FGFR3_HUMAN Fibroblast growth factorreceptor 3 (FGFR-3) (EC 2.7.10.1) (CD antigen CD333) FGFR3 JTK4 806Q6P995 F171B_HUMAN Protein FAM171B FAM171B 826 KIAA1946 NPD019 A6NFU0F187A_HUMAN Ig-like V-type domain-containing protein FAM187A FAM187A 413Q17R55 F187B_HUMAN Protein FAM187B (Transmembrane protein 162) FAM187B369 TMEM162 Q5JX71 F209A_HUMAN Protein FAM209A FAM209A 171 C20orf106Q14517 FAT1_HUMAN Protocadherin Fat 1 (Cadherin family member 7)(Cadherin-related tumor suppressor FAT1 CDHF7 FAT 4588 homolog) (Proteinfat homolog) [Cleaved into: Protocadherin Fat 1, nuclear form] Q9NYQ8FAT2_HUMAN Protocadherin Fat 2 (hFat2) (Cadherin family member 8)(Multiple epidermal growth FAT2 CDHF8 4349 factor-like domainsprotein 1) (Multiple EGF-like domains protein 1) KIAA0811 MEGF1 Q8TDW7FAT3_HUMAN Protocadherin Fat 3 (hFat3) (Cadherin family member 15) (FATtumor suppressor FAT3 CDHF15 4589 homolog 3) KIAA1989 P24071 FCAR_HUMANImmunoglobulin alpha Fc receptor (IgA Fc receptor) (CD antigen CD89)FCAR CD89 287 P12314 FCGR1_HUMAN High affinity immunoglobulin gamma Fcreceptor I (IgG Fc receptor I) (Fc-gamma RI) FCGR1A FCG1 374 (FcRI)(Fc-gamma RIA) (FcgammaRIa) (CD antigen CD64) FCGR1 IGFR1 Q96LA6FCRL1_HUMAN Fc receptor-like protein 1 (FcR-like protein 1) (FcRL1) (Fcreceptor homolog 1) (FcRH1) FCRL1 FCRH1 429 (IFGP family protein 1)(hIFGP1) (Immune receptor translocation-associated protein 5) IFGP1IRTA5 (CD antigen CD307a) Q96P31 FCRL3_HUMAN Fc receptor-like protein 3(FcR-like protein 3) (FcRL3) (Fc receptor homolog 3) (FcRH3) FCRL3 FCRH3734 (IFGP family protein 3) (hIFGP3) (Immune receptortranslocation-associated protein 3) IFGP3 IRTA3 (SH2 domain-containingphosphatase anchor protein 2) (CD antigen CD307c) SPAP2 P12318FCG2A_HUMAN Low affinity immunoglobulin gamma Fc region receptor II-a(IgG Fc receptor II-a) FCGR2A CD32 317 (CDw32) (Fc-gamma RII-a)(Fc-gamma-RIIa) (FcRII-a) (CD antigen CD32) FCG2 FCGR2A1 IGFR2 P08637FCG3A_HUMAN Low affinity immunoglobulin gamma Fc region receptor III-A(CD16a antigen) (Fc-gamma FCGR3A CD16A 254 RIII-alpha) (Fc-gamma RIII)(Fc-gamma RIIIa) (FcRIII) (FcRIIIa) (FcR-10) (IgG Fc FCG3 FCGR3 IGFR3receptor III-2) (CD antigen CD16a) Q92637 FCGRB_HUMAN High affinityimmunoglobulin gamma Fc receptor IB (IgG Fc receptor IB) (Fc-gamma RIB)FCGR1B IGFRB 280 (FcRIB) (hFcgammaRIB) Q8N441 FGRL1_HUMAN Fibroblastgrowth factor receptor-like 1 (FGF receptor-like protein 1) (FGFhomologous FGFRL1 FGFR5 FHFR 504 factor receptor) (FGFR-like protein)(Fibroblast growth factor receptor 5) (FGFR-5) UNQ480/PRO943 P12319FCERA_HUMAN High affinity immunoglobulin epsilon receptor subunit alpha(Fc-epsilon RI-alpha) (FcERI) FCER1A FCE1A 257 (IgE Fc receptor subunitalpha) Q6DN72 FCRL6_HUMAN Fc receptor-like protein 6 (FcR-like protein6) (FcRL6) (Fc receptor homolog 6) (FcRH6) FCRL6 FCRH6 434 (IFGP6)P11362 FGFR1_HUMAN Fibroblast growth factor receptor 1 (FGFR-1) (EC2.7.10.1) (Basic fibroblast growth factor FGFR1 BFGFR 822 receptor 1)(BFGFR) (bFGF-R-1) (Fms-like tyrosine kinase 2) (FLT-2) (N-sam) (Proto-CEK FGFBR FLG oncogene c-Fgr) (CD antigen CD331) FLT2 HBGFR P21802FGFR2_HUMAN Fibroblast growth factor receptor 2 (FGFR-2) (EC 2.7.10.1)(K-sam) (KGFR) FGFR2 BEK KGFR KSAM 821 (Keratinocyte growth factorreceptor) (CD antigen CD332) A6NKC4 FCGRC_HUMAN Putative high affinityimmunoglobulin gamma Fc receptor IC (IgG Fc receptor IC) (Fc-gamma RIC)FCGR1C IGFRC 280 (FcRIC) (hFcgammaRIC) Q9H6D8 FNDC4_HUMAN Fibronectintype III domain-containing protein 4 (Fibronectin type IIIrepeat-containing FNDC4 FRCP1 234 protein 1) UNQ6389/PRO21134 Q9P2B2FPRP_HUMAN Prostaglandin F2 receptor negative regulator (CD9 partner 1)(CD9P-1) (Glu-Trp-Ile EWI PTGFRN CD9P1 879 motif-containing protein F)(EWI-F) (Prostaglandin F2-alpha receptor regulatory protein) EWIF FPRP(Prostaglandin F2-alpha receptor-associated protein) (CD antigen CD315)KIAA1436 Q5SZK8 FREM2_HUMAN FRAS1-related extracellular matrix protein 2(ECM3 homolog) FREM2 3169 P22455 FGFR4_HUMAN Fibroblast growth factorreceptor 4 (FGFR-4) (EC 2.7.10.1) (CD antigen CD334) FGFR4 JTK2 TKF 802O95866 G6B_HUMAN Protein G6b G6B C6orf25 241 P49771 FLT3L_HUMANFms-related tyrosine kinase 3 ligand (Flt3 ligand) (Flt3L) (SL cytokine)FLT3LG 235 P59646 FXYD4_HUMAN FXYD domain-containing ion transportregulator 4 FXYD4 89 UNQ526/PRO1069 P36888 FLT3_HUMAN Receptor-typetyrosine-protein kinase FLT3 (EC 2.7.10.1) (FL cytokine receptor) (FetalFLT3 CD135 FLK2 STK1 993 liver kinase-2) (FLK-2) (Fms-like tyrosinekinase 3) (FLT-3) (Stem cell tyrosine kinase 1) (STK-1) (CD antigenCD135) Q8NAU1 FNDC5_HUMAN Fibronectin type III domain-containing protein5 (Fibronectin type III repeat-containing FNDC5 FRCP2 212 protein 2)[Cleaved into: Irisin] Q86XX4 FRAS1_HUMAN Extracellular matrix proteinFRAS1 FRAS1 KIAA1500 4008 P09958 FURIN_HUMAN Furin (EC 3.4.21.75)(Dibasic-processing enzyme) (Paired basic amino acid residue- FURIN FURPACE 794 cleaving enzyme) (PACE) PCSK3 Q14802 FXYD3_HUMAN FXYDdomain-containing ion transport regulator 3 (Chloride conductanceinducer protein FXYD3 MAT8 PLML 87 Mat-8) (Mammary tumor 8 kDa protein)(Phospholemman-like) Q9H0Q3 FXYD6_HUMAN FXYD domain-containing iontransport regulator 6 (Phosphohippolin) FXYD6 95 UNQ521/PRO1056 Q96DB9FXYD5_HUMAN FXYD domain-containing ion transport regulator 5(Dysadherin) FXYD5 DYSAD 178 IWU1 HSPC113 UNQ2561/PRO6241 P58550FXYD8_HUMAN Putative FXYD domain-containing ion transport regulator 8FXYD6P3 FXYD8 94 I3L273 GFY_HUMAN Golgi-associated olfactory signalingregulator (Protein Goofy) GFY 518 P06028 GLPB_HUMAN Glycophorin-B(PAS-3) (SS-active sialoglycoprotein) (Sialoglycoprotein delta) (CD GYPBGPB 91 antigen CD235b) P10912 GHR_HUMAN Growth hormone receptor (GHreceptor) (Somatotropin receptor) [Cleaved into: Growth GHR 638hormone-binding protein (GH-binding protein) (GHBP) (Serum-bindingprotein)] P15421 GLPE_HUMAN Glycophorin-E GYPE GPE 78 P13224 GP1BB_HUMANPlatelet glycoprotein Ib beta chain (GP-Ib beta) (GPIb-beta) (GPIbB)(Antigen CD42b- GP1BB 206 beta) (CD antigen CD42c) Q9NU53 GINM1_HUMANGlycoprotein integral membrane protein 1 GINM1 C6orf72 330UNQ710/PRO1361 P02724 GLPA_HUMAN Glycophorin-A (MN sialoglycoprotein)(PAS-2) (Sialoglycoprotein alpha) (CD antigen GYPA GPA 150 CD235a)Q3T906 GNPTA_HUMAN N-acetylglucosamine-1-phosphotransferase subunitsalpha/beta (EC 2.7.8.17) (GlcNAc- GNPTAB GNPTA 1256 1-phosphotransferasesubunits alpha/beta) (Stealth protein GNPTAB) (UDP-N- KIAA1208acetylglucosamine-1-phosphotransferase subunits alpha/beta) [Cleavedinto: N- acetylglucosamine-1-phosphotransferase subunit alpha;N-acetylglucosamine-1- phosphotransferase subunit beta] Q8WWB7GLMP_HUMAN Glycosylated lysosomal membrane protein (Lysosomal proteinNCU-G1) GLMP C1orf85 406 PSEC0030 UNQ2553/PRO6182 P07359 GP1BA_HUMANPlatelet glycoprotein Ib alpha chain (GP-Ib alpha) (GPIb-alpha) (GPIbA)(Glycoprotein GP1BA 652 Ibalpha) (Antigen CD42b-alpha) (CD antigenCD42b) [Cleaved into: Glycocalicin] P40197 GPV_HUMAN Plateletglycoprotein V (GPV) (Glycoprotein 5) (CD antigen CD42d) GP5 560 Q99795GPA33_HUMAN Cell surface A33 antigen (Glycoprotein A33) GPA33 319 P14770GPIX_HUMAN Platelet glycoprotein IX (GP-IX) (GPIX) (Glycoprotein 9) (CDantigen CD42a) GP9 177 Q86XS8 GOLI_HUMAN E3 ubiquitin-protein ligaseRNF130 (EC 6.3.2.—) (Goliath homolog) (H-Goliath) (RING RNF130 419finger protein 130) P25092 GUC2C_HUMAN Heat-stable enterotoxin receptor(STA receptor) (hSTAR) (EC 4.6.1.2) (Guanylyl cyclase GUCY2C GUC2C STAR1073 C) (GC-C) (Intestinal guanylate cyclase) Q14789 GOGB1_HUMAN Golginsubfamily B member 1 (372 kDa Golgi complex-associated protein) (GCP372)GOLGB1 3259 (Giantin) (Macrogolgin) Q14956 GPNMB_HUMAN Transmembraneglycoprotein NMB (Transmembrane glycoprotein HGFIN) GPNMB HGFIN NMB 572UNQ1725/PRO9925 P51841 GUC2F_HUMAN Retinal guanylyl cyclase 2 (RETGC-2)(EC 4.6.1.2) (Guanylate cyclase 2F, retinal) GUCY2F GUC2F 1108(Guanylate cyclase F) (GC-F) (Rod outer segment membrane guanylatecyclase 2) RETGC2 (ROS-GC2) Q92643 GPI8_HUMAN GPI-anchor transamidase(GPI transamidase) (EC 3.—.—.—) (GPI8 homolog) (hGPI8) PIGK GPI8 395(Phosphatidylinositol-glycan biosynthesis class K protein) (PIG-K)Q02846 GUC2D_HUMAN Retinal guanylyl cyclase 1 (RETGC-1) (EC 4.6.1.2)(Guanylate cyclase 2D, retinal) (Rod GUCY2D CORD6 1103 outer segmentmembrane guanylate cyclase) (ROS-GC) GUC1A4 GUC2D RETGC RETGC1 Q9UBK5HCST_HUMAN Hematopoietic cell signal transducer (DNAX-activation protein10) (Membrane protein HCST DAP10 93 DAP10) (Transmembrane adapterprotein KAP10) KAP10 PIK3AP UNQ587/PRO1157 Q14CZ8 HECAM_HUMAN Hepatocytecell adhesion molecule (Protein hepaCAM) HEPACAM 416 A8MVW5 HECA2_HUMANHEPACAM family member 2 (Mitotic kinetics regulator) HEPACAM2 MIKI 462UNQ305/PRO346 Q9ULI3 HEG1_HUMAN Protein HEG homolog 1 HEG1 KIAA1237 1381Q92896 GSLG1_HUMAN Golgi apparatus protein 1 (CFR-1) (Cysteine-richfibroblast growth factor receptor) (E- GLG1 CFR1 ESL1 1179 selectinligand 1) (ESL-1) (Golgi sialoglycoprotein MG-160) MG160 Q99075HBEGF_HUMAN Proheparin-binding EGF-like growth factor [Cleaved into:Heparin-binding EGF-like HBEGF DTR DTS 208 growth factor (HB-EGF)(HBEGF) (Diphtheria toxin receptor) (DT-R)] HEGFL Q96D42 HAVR1_HUMANHepatitis A virus cellular receptor 1 (HAVcr-1) (Kidney injurymolecule 1) (KIM-1) (T-cell HAVCR1 KIM1 359 immunoglobulin and mucindomain-containing protein 1) (TIMD-1) (T-cell immunoglobulin TIM1 TIMD1mucin receptor 1) (TIM) (TIM-1) (T-cell membrane protein 1) Q8TDQ0HAVR2_HUMAN Hepatitis A virus cellular receptor 2 (HAVcr-2) (T-cellimmunoglobulin and mucin domain- HAVCR2 TIM3 301 containing protein 3)(TIMD-3) (T-cell immunoglobulin mucin receptor 3) (TIM-3) (T-cell TIMD3membrane protein 3) Q30201 HFE_HUMAN Hereditary hemochromatosis protein(HLA-H) HFE HLAH 348 P30511 HLAF_HUMAN HLA class I histocompatibilityantigen, alpha chain F (CDA12) (HLA F antigen) HLA-F HLA-5.4 346(Leukocyte antigen F) (MHC class I antigen F) HLAF A8MVS5 HIDE1_HUMANProtein HIDE1 HIDE1 C19orf38 230 P13747 HLAE_HUMAN HLA class Ihistocompatibility antigen, alpha chain E (MHC class I antigen E) HLA-EHLA-6.2 358 HLAE Q9BQS7 HEPH_HUMAN Hephaestin (EC 1.—.—.—) HEPH KIAA06981158 UNQ2562/PRO6242 Q95460 HMR1_HUMAN Major histocompatibility complexclass I-related gene protein (MHC class I-related gene MR1 341 protein)(Class I histocompatibility antigen-like protein) Q6MZM0 HPHL1_HUMANHephaestin-like protein 1 (EC 1.—.—.—) HEPHL1 1159 Q9UM44 HHLA2_HUMANHERV-H LTR-associating protein 2 (Human endogenous retrovirus-H longterminal HHLA2 414 repeat-associating protein 2) P17693 HLAG_HUMAN HLAclass I histocompatibility antigen, alpha chain G (HLA G antigen) (MHCclass I HLA-G HLA-6.0 338 antigen G) HLAG Q08334 I10R2_HUMANInterleukin-10 receptor subunit beta (IL-10 receptor subunit beta)(IL-10R subunit beta) IL10RB CRFB4 325 (IL-10RB) (Cytokine receptorclass-II member 4) (Cytokine receptor family 2 member 4) D21S58 D21S66(CRF2-4) (Interleukin-10 receptor subunit 2) (IL-10R subunit 2)(IL-10R2) (CD antigen CDw210b) Q96F46 I17RA_HUMAN Interleukin-17receptor A (IL-17 receptor A) (IL-17RA) (CDw217) (CD antigen CD217)IL17RA IL17R 866 Q99665 I12R2_HUMAN Interleukin-12 receptor subunitbeta-2 (IL-12 receptor subunit beta-2) (IL-12R subunit IL12RB2 862beta-2) (IL-12R-beta-2) (IL-12RB2) Q14627 I13R2_HUMAN Interleukin-13receptor subunit alpha-2 (IL-13 receptor subunit alpha-2) (IL-13Rsubunit IL13RA2 IL13R 380 alpha-2) (IL-13R-alpha-2) (IL-13RA2)(Interleukin-13-binding protein) (CD antigen CD213a2) Q9NRM6 I17RB_HUMANInterleukin-17 receptor B (IL-17 receptor B) (IL-17RB) (Cytokinereceptor-like 4) (IL-17 IL17RB CRL4 502 receptor homolog 1) (IL-17RM)(IL17Rh1) (Interleukin-17B receptor) (IL-17B receptor) EVI27 IL17BRUNQ2501/PRO19612 Q8NFM7 I17RD_HUMAN Interleukin-17 receptor D (IL-17receptor D) (IL-17RD) (IL17Rhom) (Interleukin-17 IL17RD IL17RLM SEF 739receptor-like protein) (Set homolog) (hSef) UNQ6115/PRO20026 Q8N6P7I22R1_HUMAN Interleukin-22 receptor subunit alpha-1 (IL-22 receptorsubunit alpha-1) (IL-22R-alpha-1) IL22RA1 IL22R 574 (IL-22RA1) (Cytokinereceptor class-II member 9) (Cytokine receptor family 2 member 9)(CRF2-9) (ZcytoR11) Q9UMF0 ICAM5_HUMAN Intercellular adhesion molecule 5(ICAM-5) (Telencephalin) ICAM5 TLCN TLN 924 P42701 I12R1_HUMANInterleukin-12 receptor subunit beta-1 (IL-12 receptor subunit beta-1)(IL-12R subunit IL12RB1 IL12R 662 beta-1) (IL-12R-beta-1) (IL-12RB1)(IL-12 receptor beta component) (CD antigen CD212) IL12RB P78552I13R1_HUMAN Interleukin-13 receptor subunit alpha-1 (IL-13 receptorsubunit alpha-1) (IL-13R subunit IL13RA1 IL13R 427 alpha-1)(IL-13R-alpha-1) (IL-13RA1) (Cancer/testis antigen 19) (CT19) (CDantigen IL13RA CD213a1) Q8NFR9 I17RE_HUMAN Interleukin-17 receptor E(IL-17 receptor E) (IL-17RE) IL17RE 667 UNQ3056/PRO9877 O95256I18RA_HUMAN Interleukin-18 receptor accessory protein (IL-18 receptoraccessory protein) (IL-18RAcP) IL18RAP IL1R7 599 (Accessoryprotein-like) (AcPL) (CD218 antigen-like family member B) (CDw218b)(IL-1R accessory protein-like) (IL-1RAcPL) (Interleukin-1 receptor 7)(IL-1R-7) (IL-1R7) (Interleukin-18 receptor accessory protein-like)(Interleukin-18 receptor beta) (IL-18R- beta) (IL-18Rbeta) (CD antigenCD218b) Q6UXL0 I20RB_HUMAN Interleukin-20 receptor subunit beta (IL-20receptor subunit beta) (IL-20R-beta) (IL-20RB) IL20RB DIRS1 311(Fibronectin type III domain containing 6) (FNDC6) (IL-20R2)UNQ557/PRO1114 P32942 ICAM3_HUMAN Intercellular adhesion molecule 3(ICAM-3) (CDw50) (ICAM-R) (CD antigen CD50) ICAM3 547 Q13261 I15RA_HUMANInterleukin-15 receptor subunit alpha (IL-15 receptor subunit alpha)(IL-15R-alpha) (IL- IL15RA 267 15RA) (CD antigen CD215) [Cleaved into:Soluble interleukin-15 receptor subunit alpha (sIL-15 receptor subunitalpha) (sIL-15R-alpha) (sIL-15RA)] Q9H2X8 I27L2_HUMAN Interferonalpha-inducible protein 27-like protein 2 (Interferon-stimulated gene12b IFI27L2 FAM14A 130 protein) (ISG12(b)) (Protein TLH29) (pIFI27-likeprotein) TLH29 Q9Y6W8 ICOS_HUMAN Inducible T-cell costimulator(Activation-inducible lymphocyte immunomediatory ICOS AILIM 199molecule) (CD antigen CD278) P13598 ICAM2_HUMAN Intercellular adhesionmolecule 2 (ICAM-2) (CD antigen CD102) ICAM2 275 P98153 IDD_HUMANIntegral membrane protein DGCR2/IDD DGCR2 IDD 550 KIAA0163 O75054IGSF3_HUMAN Immunoglobulin superfamily member 3 (IgSF3) (Glu-Trp-Ile EWImotif-containing protein IGSF3 EWI3 1194 3) (EWI-3) KIAA0466 P01589IL2RA_HUMAN Interleukin-2 receptor subunit alpha (IL-2 receptor subunitalpha) (IL-2-RA) (IL-2R subunit IL2RA 272 alpha) (IL2-RA) (TAC antigen)(p55) (CD antigen CD25) P26951 IL3RA_HUMAN Interleukin-3 receptorsubunit alpha (IL-3 receptor subunit alpha) (IL-3R subunit alpha) IL3RAIL3R 378 (IL-3R-alpha) (IL-3RA) (CD antigen CD123) P24394 IL4RA_HUMANInterleukin-4 receptor subunit alpha (IL-4 receptor subunit alpha)(IL-4R subunit alpha) IL4R IL4RA 582J2.1 825 (IL-4R-alpha) (IL-4RA) (CDantigen CD124) [Cleaved into: Soluble interleukin-4 receptor subunitalpha (Soluble IL-4 receptor subunit alpha) (Soluble IL-4R-alpha)(sIL4Ralpha/prot) (IL-4-binding protein) (IL4-BP)] Q8NAC3 I17RC_HUMANInterleukin-17 receptor C (IL-17 receptor C) (IL-17RC) (Interleukin-17receptor homolog) IL17RC 791 (IL17Rhom) (Interleukin-17 receptor-likeprotein) (IL-17RL) (ZcytoR14) UNQ6118/PRO20040/ PRO38901 Q9UHF4I20RA_HUMAN Interleukin-20 receptor subunit alpha (IL-20 receptorsubunit alpha) (IL-20R-alpha) (IL- IL20RA 553 20RA) (Cytokine receptorclass-II member 8) (Cytokine receptor family 2 member 8) UNQ681/PRO1315(CRF2-8) (IL-20R1) (ZcytoR7) Q6UWB1 I27RA_HUMAN Interleukin-27 receptorsubunit alpha (IL-27 receptor subunit alpha) (IL-27R subunit IL27RA CRL1636 alpha) (IL-27R-alpha) (IL-27RA) (Cytokine receptor WSX-1) (Cytokinereceptor-like 1) TCCR WSX1 (Type I T-cell cytokine receptor) (TCCR)(ZcytoR1) UNQ296/PRO336 Q9H665 IGFR1_HUMAN IGF-like family receptor 1(Transmembrane protein 149) (U2 small nuclear RNA auxiliary IGFLR1TMEM149 355 factor 1-like 4) U2AF1L4 P01880 IGHD_HUMAN Ig delta chain Cregion IGHD 384 Q5DX21 IGS11_HUMAN Immunoglobulin superfamily member 11(IgSF11) (Brain and testis-specific IGSF11 BTIGSF 431 immunoglobulinsuperfamily protein) (Bt-IGSF) (V-set and immunoglobulin domain- CXADRL1VSIG3 containing protein 3) Q93033 IGSF2_HUMAN Immunoglobulinsuperfamily member 2 (IgSF2) (Cell surface glycoprotein V7) (Glu-Trp-IleCD101 EWI101 1021 EWI motif-containing protein 101) (EWI-101) (CDantigen CD101) IGSF2 V7 Q9HBE5 IL21R_HUMAN Interleukin-21 receptor(IL-21 receptor) (IL-21R) (Novel interleukin receptor) (CD antigen IL21RNILR 538 CD360) UNQ3121/PRO10273 Q71H61 ILDR2_HUMAN Immunoglobulin-likedomain-containing receptor 2 ILDR2 C1orf32 639 O75144 ICOSL_HUMAN ICOSligand (B7 homolog 2) (B7-H2) (B7-like protein GI50) (B7-relatedprotein 1) (B7RP- ICOSLG B7H2 302 1) (CD antigen CD275) B7RP1 ICOSLKIAA0653 Q8TDY8 IGDC4_HUMAN Immunoglobulin superfamily DCC subclassmember 4 (Neighbor of punc e11) (Protein IGDCC4 DDM36 1250 DDM36)(hDDM36) KIAA1628 NOPE P01871 IGHM_HUMAN Ig mu chain C region IGHM 452O95976 IGSF6_HUMAN Immunoglobulin superfamily member 6 (IgSF6) (ProteinDORA) IGSF6 DORA 241 Q9NPH3 IL1AP_HUMAN Interleukin-1 receptor accessoryprotein (IL-1 receptor accessory protein) (IL-1RAcP) IL1RAP C3orf13 570(Interleukin-1 receptor 3) (IL-1R-3) (IL-1R3) IL1R3 P31785 IL2RG_HUMANCytokine receptor common subunit gamma (Interleukin-2 receptor subunitgamma) (IL-2 IL2RG 369 receptor subunit gamma) (IL-2R subunit gamma)(IL-2RG) (gammaC) (p64) (CD antigen CD132) P32927 IL3RB_HUMAN Cytokinereceptor common subunit beta (CDw131) (GM-CSF/IL-3/IL-5 receptor commonCSF2RB IL3RB 897 beta subunit) (CD antigen CD131) IL5RB Q01113IL9R_HUMAN Interleukin-9 receptor (IL-9 receptor) (IL-9R) (CD antigenCD129) IL9R 521 Q9HB29 ILRL2_HUMAN Interleukin-1 receptor-like 2 (IL-36receptor) (IL-36R) (Interleukin-1 receptor-related IL1RL2 IL1RRP2 575protein 2) (IL-1Rrp2) (IL1R-rp2) P15260 INGR1_HUMAN Interferon gammareceptor 1 (IFN-gamma receptor 1) (IFN-gamma-R1) (CDw119) (CD IFNGR1 489antigen CD119) Q13651 I10R1_HUMAN Interleukin-10 receptor subunit alpha(IL-10 receptor subunit alpha) (IL-10R subunit IL10RA IL10R 578 alpha)(IL-10RA) (CDw210a) (Interleukin-10 receptor subunit 1) (IL-10Rsubunit 1) (IL- 10R1) (CD antigen CD210) Q14626 I11RA_HUMANInterleukin-11 receptor subunit alpha (IL-11 receptor subunit alpha)(IL-11R subunit IL11RA 422 alpha) (IL-11R-alpha) (IL-11RA) P05362ICAM1_HUMAN Intercellular adhesion molecule 1 (ICAM-1) (Major grouprhinovirus receptor) (CD antigen CD54) ICAM1 532 Q14773 ICAM4_HUMANIntercellular adhesion molecule 4 (ICAM-4) (Landsteiner-Wiener bloodgroup ICAM4 LW 271 glycoprotein) (LW blood group protein) (CD antigenCD242) Q9NSI5 IGSF5_HUMAN Immunoglobulin superfamily member 5 (IgSF5)(Junctional adhesion molecule 4) (JAM-4) IGSF5 JAM4 407 P14778IL1R1_HUMAN Interleukin-1 receptor type 1 (IL-1R-1) (IL-1RT-1) (IL-1RT1)(CD121 antigen-like family IL1R1 IL1R IL1RA 569 member A) (Interleukin-1receptor alpha) (IL-1R-alpha) (Interleukin-1 receptor type I) IL1RT1(p80) (CD antigen CD121a) [Cleaved into: Interleukin-1 receptor type 1,membrane form (mIL-1R1) (mIL-1RI); Interleukin-1 receptor type 1,soluble form (sIL-1R1) (sIL-1RI)] Q8NI17 IL31R_HUMAN Interleukin-31receptor subunit alpha (IL-31 receptor subunit alpha) (IL-31R subunitIL31RA CRL3 GPL 732 alpha) (IL-31R-alpha) (IL-31RA) (Cytokinereceptor-like 3) (GLM-R) (hGLM-R) (Gp130- UNQ6368/PRO21073/ likemonocyte receptor) (Gp130-like receptor) (ZcytoR17) PRO21384 Q01344IL5RA_HUMAN Interleukin-5 receptor subunit alpha (IL-5 receptor subunitalpha) (IL-5R subunit alpha) IL5RA IL5R 420 (IL-5R-alpha) (IL-5RA)(CDw125) (CD antigen CD125) P16871 IL7RA_HUMAN Interleukin-7 receptorsubunit alpha (IL-7 receptor subunit alpha) (IL-7R subunit alpha) IL7R459 (IL-7R-alpha) (IL-7RA) (CDw127) (CD antigen CD127) P08887IL6RA_HUMAN Interleukin-6 receptor subunit alpha (IL-6 receptor subunitalpha) (IL-6R subunit alpha) IL6R 468 (IL-6R-alpha) (IL-6RA) (IL-6R 1)(Membrane glycoprotein 80) (gp80) (CD antigen CD126) Q01638 ILRL1_HUMANInterleukin-1 receptor-like 1 (Protein ST2) IL1RL1 DER4 ST2 556 T1P06213 INSR_HUMAN Insulin receptor (IR) (EC 2.7.10.1) (CD antigen CD220)[Cleaved into: Insulin receptor INSR 1382 subunit alpha; Insulinreceptor subunit beta] P08069 IGF1R_HUMAN Insulin-like growth factor 1receptor (EC 2.7.10.1) (Insulin-like growth factor I receptor) IGF1R1367 (IGF-I receptor) (CD antigen CD221) [Cleaved into: Insulin-likegrowth factor 1 receptor alpha chain; Insulin-like growth factor 1receptor beta chain] P14784 IL2RB_HUMAN Interleukin-2 receptor subunitbeta (IL-2 receptor subunit beta) (IL-2R subunit beta) (IL- IL2RB 5512RB) (High affinity IL-2 receptor subunit beta) (p70-75) (p75) (CDantigen CD122) Q86SU0 ILDR1_HUMAN Immunoglobulin-like domain-containingreceptor 1 ILDR1 546 P14616 INSRR_HUMAN Insulin receptor-related protein(IRR) (EC 2.7.10.1) (IR-related receptor) [Cleaved into: INSRR IRR 1297Insulin receptor-related protein alpha chain; Insulin receptor-relatedprotein beta chain] Q13478 IL18R_HUMAN Interleukin-18 receptor 1(IL-18R-1) (IL-18R1) (CD218 antigen-like family member A) IL18R1 IL1RRP541 (CDw218a) (IL1 receptor-related protein) (IL-1Rrp) (IL1R-rp) (CDantigen CD218a) Q5VWK5 IL23R_HUMAN Interleukin-23 receptor (IL-23receptor) (IL-23R) IL23R 629 Q9BZV3 IMPG2_HUMAN Interphotoreceptormatrix proteoglycan 2 (Interphotoreceptor matrix proteoglycan of 200IMPG2 IPM200 1241 kDa) (IPM 200) (Sialoprotein associated with cones androds proteoglycan) (Spacrcan) Q8IU57 INLR1_HUMAN Interferon lambdareceptor 1 (IFN-lambda receptor 1) (IFN-lambda-R1) (Cytokine IFNLR1IL28RA 520 receptor class-II member 12) (Cytokine receptor family 2member 12) (CRF2-12) LICR2 (Interleukin-28 receptor subunit alpha)(IL-28 receptor subunit alpha) (IL-28R-alpha) (IL- 28RA) (Likelyinterleukin or cytokine receptor 2) (LICR2) Q6GPH6 IPIL1_HUMAN Inositol1,4,5-trisphosphate receptor-interacting protein-like 1 ITPRIPL1 555KIAA1754L Q9NP60 IRPL2_HUMAN X-linked interleukin-1 receptor accessoryprotein-like 2 (IL-1 receptor accessory protein- IL1RAPL2 IL1R9 686 like2) (IL-1-RAPL-2) (IL-1RAPL-2) (IL1RAPL-2) (IL1RAPL-2-related protein)(Interleukin- 1 receptor 9) (IL-1R-9) (IL-1R9) (Three immunoglobulindomain-containing IL-1 receptor- related 1) (TIGIRR-1) Q8IVU1IGDC3_HUMAN Immunoglobulin superfamily DCC subclass member 3 (Putativeneuronal cell adhesion IGDCC3 PUNC 814 molecule) P17181 INAR1_HUMANInterferon alpha/beta receptor 1 (IFN-R-1) (IFN-alpha/beta receptor 1)(Cytokine receptor IFNAR1 IFNAR 557 class-II member 1) (Cytokinereceptor family 2 member 1) (CRF2-1) (Type I interferon receptor 1)Q13683 ITA7_HUMAN Integrin alpha-7 [Cleaved into: Integrin alpha-7 heavychain; Integrin alpha-7 light chain; ITGA7 1181 Integrin alpha-7 70 kDaform] UNQ406/PRO768 P53708 ITA8_HUMAN Integrin alpha-8 [Cleaved into:Integrin alpha-8 heavy chain; Integrin alpha-8 light chain] ITGA8 1063Q13349 ITAD_HUMAN Integrin alpha-D (ADB2) (CD11 antigen-like familymember D) (Leukointegrin alpha D) ITGAD 1161 (CD antigen CD11d) P06756ITAV_HUMAN Integrin alpha-V (Vitronectin receptor subunit alpha) (CDantigen CD51) [Cleaved into: ITGAV MSK8 VNRA 1048 Integrin alpha-V heavychain; Integrin alpha-V light chain] Q6UXV1 IZUM2_HUMAN Izumo sperm-eggfusion protein 2 IZUMO2 C19orf41 221 SCRL UNQ6978/PRO21961 P27930IL1R2_HUMAN Interleukin-1 receptor type 2 (IL-1R-2) (IL-1RT-2) (IL-1RT2)(CD121 antigen-like family IL1R2 IL1RB 398 member B) (CDw121b) (IL-1type II receptor) (Interleukin-1 receptor beta) (IL-1R-beta)(Interleukin-1 receptor type II) (CD antigen CD121b) [Cleaved into:Interleukin-1 receptor type 2, membrane form (mIL-1R2) (mIL-1RII);Interleukin-1 receptor type 2, soluble form (sIL-1R2) (sIL-1RII)] P40189IL6RB_HUMAN Interleukin-6 receptor subunit beta (IL-6 receptor subunitbeta) (IL-6R subunit beta) (IL- IL6ST 918 6R-beta) (IL-6RB) (CDw130)(Interleukin-6 signal transducer) (Membrane glycoprotein 130) (gp130)(Oncostatin-M receptor subunit alpha) (CD antigen CD130) P17301ITA2_HUMAN Integrin alpha-2 (CD49 antigen-like family member B)(Collagen receptor) (Platelet ITGA2 CD49B 1181 membrane glycoprotein Ia)(GPIa) (VLA-2 subunit alpha) (CD antigen CD49b) P26006 ITA3_HUMANIntegrin alpha-3 (CD49 antigen-like family member C) (FRP-2)(Galactoprotein B3) ITGA3 MSK18 1051 (GAPB3) (VLA-3 subunit alpha) (CDantigen CD49c) [Cleaved into: Integrin alpha-3 heavy chain; Integrinalpha-3 light chain] P11215 ITAM_HUMAN Integrin alpha-M (CD11antigen-like family member B) (CR-3 alpha chain) (Cell surface ITGAMCD11B 1152 glycoprotein MAC-1 subunit alpha) (Leukocyte adhesionreceptor MO1) (Neutrophil CR3A adherence receptor) (CD antigen CD11b)P16144 ITB4_HUMAN Integrin beta-4 (GP150) (CD antigen CD104) ITGB4 1822O75578 ITA10_HUMAN Integrin alpha-10 ITGA10 1167 UNQ468/PRO827 P56199ITA1_HUMAN Integrin alpha-1 (CD49 antigen-like family member A) (Lamininand collagen receptor) ITGA1 1179 (VLA-1) (CD antigen CD49a) P08514ITA2B_HUMAN Integrin alpha-IIb (GPalpha IIb) (GPIIb) (Platelet membraneglycoprotein IIb) (CD antigen ITGA2B GP2B 1039 CD41) [Cleaved into:Integrin alpha-IIb heavy chain; Integrin alpha-IIb light chain, form 1;ITGAB Integrin alpha-IIb light chain, form 2] P08648 ITA5_HUMAN Integrinalpha-5 (CD49 antigen-like family member E) (Fibronectin receptorsubunit alpha) ITGA5 FNRA 1049 (Integrin alpha-F) (VLA-5) (CD antigenCD49e) [Cleaved into: Integrin alpha-5 heavy chain; Integrin alpha-5light chain] P38570 ITAE_HUMAN Integrin alpha-E (HML-1 antigen)(Integrin alpha-IEL) (Mucosal lymphocyte 1 antigen) ITGAE 1179 (CDantigen CD103) [Cleaved into: Integrin alpha-E light chain: Integrinalpha-E heavy chain] P20702 ITAX_HUMAN Integrin alpha-X (CD11antigen-like family member C) (Leu M5) (Leukocyte adhesion ITGAX CD11C1163 glycoprotein p150, 95 alpha chain) (Leukocyte adhesion receptorp150, 95) (CD antigen CD11c) P05106 ITB3_HUMAN Integrin beta-3 (Plateletmembrane glycoprotein IIIa) (GPIIIa) (CD antigen CD61) ITGB3 GP3A 788Q5VZ72 IZUM3_HUMAN Izumo sperm-egg fusion protein 3 IZUMO3 C9orf134 239P78504 JAG1_HUMAN Protein jagged-1 (Jagged1) (hJ1) (CD antigen CD339)JAG1 JAGL1 1218 A8MWY0 K132L_HUMAN UPF0577 protein KIAA1324-like(Estrogen-induced gene 121-like protein) (hEIG121L) KIAA1324L 1029EIG121L P48551 INAR2_HUMAN Interferon alpha/beta receptor 2 (IFN-R-2)(IFN-alpha binding protein) (IFN-alpha/beta IFNAR2 IFNABR 515 receptor2) (Interferon alpha binding protein) (Type I interferon receptor 2)IFNARB P38484 INGR2_HUMAN Interferon gamma receptor 2 (IFN-gammareceptor 2) (IFN-gamma-R2) (Interferon IFNGR2 IFNGT1 337 gamma receptoraccessory factor 1) (AF-1) (Interferon gamma transducer 1) Q3MIP1IPIL2_HUMAN Inositol 1,4,5-trisphosphate receptor-interactingprotein-like 2 ITPRIPL2 535 Q6UXG2 K1324_HUMAN UPF0577 protein KIAA1324(Estrogen-induced gene 121 protein) KIAA1324 EIG121 1013 UNQ2426/PRO4985Q3SXP7 K1644_HUMAN Uncharacterized protein KIAA1644 KIAA1644 199 Q9NZN1IRPL1_HUMAN Interleukin-1 receptor accessory protein-like 1(IL-1-RAPL-1) (IL-1RAPL-1) (IL1RAPL-1) IL1RAPL1 OPHN4 696(Oligophrenin-4) (Three immunoglobulin domain-containing IL-1receptor-related 2) (TIGIRR-2) (X-linked interleukin-1 receptoraccessory protein-like 1) Q9UKX5 ITA11_HUMAN Integrin alpha-11 ITGA11MSTP018 1188 P05556 ITB1_HUMAN Integrin beta-1 (Fibronectin receptorsubunit beta) (Glycoprotein IIa) (GPIIA) (VLA-4 ITGB1 FNRB MDF2 798subunit beta) (CD antigen CD29) MSK12 P05107 ITB2_HUMAN Integrin beta-2(Cell surface adhesion glycoproteins LFA-1/CR3/p150, 95 subunit beta)ITGB2 CD18 MFI7 769 (Complement receptor C3 subunit beta) (CD antigenCD18) P18564 ITB6_HUMAN Integrin beta-6 ITGB6 788 P26010 ITB7_HUMANIntegrin beta-7 (Gut homing receptor beta subunit) ITGB7 798 P26012ITB8_HUMAN Integrin beta-8 ITGB8 769 Q9Y624 JAM1_HUMAN Junctionaladhesion molecule A (JAM-A) (Junctional adhesion molecule 1) (JAM-1)F11R JAM1 JCAM 299 (Platelet F11 receptor) (Platelet adhesionmolecule 1) (PAM-1) (CD antigen CD321) UNQ264/PRO301 Q9BX67 JAM3_HUMANJunctional adhesion molecule C (JAM-C) (JAM-2) (Junctional adhesionmolecule 3) JAM3 310 (JAM-3) UNQ859/PRO1868 Q8IYV9 IZUM1_HUMAN Izumosperm-egg fusion protein 1 (Oocyte binding/fusion factor) (OBF)(Sperm-specific IZUMO1 350 protein izumo) Q9UJ90 KCNE5_HUMAN Potassiumvoltage-gated channel subfamily E regulatory beta subunit 5 (AMME KCNE5AMMECR2 142 syndrome candidate gene 2 protein) (Potassium channelsubunit beta MiRP4) (Potassium KCNE1L voltage-gated channel subfamily Emember 1-like protein) P13612 ITA4_HUMAN Integrin alpha-4 (CD49antigen-like family member D) (Integrin alpha-IV) (VLA-4 subunit ITGA4CD49D 1032 alpha) (CD antigen CD49d) P23229 ITA6_HUMAN Integrin alpha-6(CD49 antigen-like family member F) (VLA-6) (CD antigen CD49f) ITGA61130 [Cleaved into: Integrin alpha-6 heavy chain; Integrin alpha-6 lightchain; Processed integrin alpha-6 (Alpha6p)] Q13797 ITA9_HUMAN Integrinalpha-9 (Integrin alpha-RLC) ITGA9 1035 P20701 ITAL_HUMAN Integrinalpha-L (CD11 antigen-like family member A) (Leukocyte adhesionglycoprotein ITGAL CD11A 1170 LFA-1 alpha chain) (LFA-1A) (Leukocytefunction-associated molecule 1 alpha chain) (CD antigen CD11a) P18084ITB5_HUMAN Integrin beta-5 ITGB5 799 Q9Y219 JAG2_HUMAN Protein jagged-2(Jagged2) (hJ2) JAG2 1238 Q5VV43 K0319_HUMAN Dyslexia-associated proteinKIAA0319 KIAA0319 1072 Q8IYS2 K2013_HUMAN Uncharacterized proteinKIAA2013 KIAA2013 634 P57087 JAM2_HUMAN Junctional adhesion molecule B(JAM-B) (Junctional adhesion molecule 2) (JAM-2) JAM2 C21orf43 298(Vascular endothelial junction-associated molecule) (VE-JAM) (CD antigenCD322) VEJAM UNQ219/PRO245 Q86YT9 JAML_HUMAN Junctional adhesionmolecule-like (Adhesion molecule interacting with CXADR antigen 1) JAMLAMICA1 394 (Dendritic cell-specific protein CREA7-1) UNQ722/PRO1387A0A087 KCE1B_HUMAN Potassium voltage-gated channel subfamily E member 1BKCNE1B 132 WTH5 Q8NC54 KCT2_HUMAN Keratinocyte-associated transmembraneprotein 2 KCT2 C5orf15 265 HTGN29 Q6UWL6 KIRR2_HUMAN Kin of IRRE-likeprotein 2 (Kin of irregular chiasm-like protein 2) (Nephrin-like protein3) KIRREL2 NEPH3 708 UNQ5827/PRO19646 O76095 JTB_HUMAN Protein JTB(Jumping translocation breakpoint protein) (Prostate androgen-regulatedJTB HSPC222 146 protein) (PAR protein) Q9Y6J6 KCNE2_HUMAN Potassiumvoltage-gated channel subfamily E member 2 (MinK-related peptide 1)KCNE2 123 (Minimum potassium ion channel-related peptide 1) (Potassiumchannel subunit beta MiRP1) Q9Y6H6 KCNE3_HUMAN Potassium voltage-gatedchannel subfamily E member 3 (MinK-related peptide 2) KCNE3 103 (Minimumpotassium ion channel-related peptide 2) (Potassium channel subunit betaMiRP2) Q8NHK3 KI2LB_HUMAN Killer cell immunoglobulin-like receptor 2DL5B(CD158 antigen-like family member F2) KIR2DL5B CD158F 375 (Killer cellimmunoglobulin-like receptor 2DLX) (CD antigen CD158f2) CD158F2 KIR2DL5KIR2DLX Q14952 KI2S3_HUMAN Killer cell immunoglobulin-like receptor 2DS3(MHC class I NK cell receptor) (Natural KIR2DS3 NKAT7 304killer-associated transcript 7) (NKAT-7) Q14943 KI3S1_HUMAN Killer cellimmunoglobulin-like receptor 3DS1 (MHC class I NK cell receptor)(Natural KIR3DS1 NKAT10 387 killer-associated transcript 10) (NKAT-10)Q9NRX6 KISHB_HUMAN Protein kish-B (Transmembrane protein 167B) TMEM167B74 C1orf119 AD-020 P15382 KCNE1_HUMAN Potassium voltage-gated channelsubfamily E member 1 (Delayed rectifier potassium KCNE1 129 channelsubunit IsK) (IKs producing slow voltage-gated potassium channel subunitbeta Mink) (Minimal potassium channel) P43626 KI2L1_HUMAN Killer cellimmunoglobulin-like receptor 2DL1 (CD158 antigen-like family member A)KIR2DL1 CD158A 348 (MHC class I NK cell receptor) (Naturalkiller-associated transcript 1) (NKAT-1) (p58 NKAT1 natural killer cellreceptor clones CL-42/47.11) (p58 NK receptor CL-42/47.11) (p58.1 MHCclass-I-specific NK receptor) (CD antigen CD158a) Q99706 KI2L4_HUMANKiller cell immunoglobulin-like receptor 2DL4 (CD158 antigen-like familymember D) KIR2DL4 CD158D 377 (G9P) (Killer cell inhibitory receptor103AS) (KIR-103AS) (MHC class I NK cell receptor KIR103AS KIR103AS) (CDantigen CD158d) P43632 KI2S4_HUMAN Killer cell immunoglobulin-likereceptor 2DS4 (CD158 antigen-like family member I) (MHC KIR2DS4 CD158I304 class I NK cell receptor) (Natural killer-associated transcript 8)(NKAT-8) (P58 natural KKA3 NKAT8 killer cell receptor clonesCL-39/CL-17) (p58 NK receptor CL-39/CL-17) (CD antigen CD158i) Q8IZU9KIRR3_HUMAN Kin of IRRE-like protein 3 (Kin of irregular chiasm-likeprotein 3) (Nephrin-like protein 2) KIRREL3 KIAA1867 778 [Cleaved into:Processed kin of IRRE-like protein 3] NEPH2 UNQ5923/PRO4502/ PRO19814P32004 L1CAM_HUMAN Neural cell adhesion molecule L1 (N-CAM-L1) (NCAM-L1)(CD antigen CD171) L1CAM CAML1 1257 MIC5 Q6GTX8 LAIR1_HUMANLeukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) (hLAIR1)(CD antigen LAIR1 CD305 287 CD305) P43628 KI2L3_HUMAN Killer cellimmunoglobulin-like receptor 2DL3 (CD158 antigen-like family member B2)KIR2DL3 CD158B2 341 (KIR-023GB) (Killer inhibitory receptor cl 2-3) (MHCclass I NK cell receptor) (NKAT2a) KIRCL23 NKAT2 (NKAT2b) (Naturalkiller-associated transcript 2) (NKAT-2) (p58 natural killer cellreceptor clone CL-6) (p58 NK receptor CL-6) (p58.2 MHC class-I-specificNK receptor) (CD antigen CD158b2) Q14954 KI2S1_HUMAN Killer cellimmunoglobulin-like receptor 2DS1 (CD158 antigen-like family member H)KIR2DS1 CD158H 304 (MHC class I NK cell receptor Eb6 Actl) (CD antigenCD158h) Q14953 KI2S5_HUMAN Killer cell immunoglobulin-like receptor 2DS5(CD158 antigen-like family member G) KIR2DS5 CD158G 304 (MHC class I NKcell receptor) (Natural killer-associated transcript 9) (NKAT-9) (CDNKAT9 antigen CD158g) P43629 KI3L1_HUMAN Killer cell immunoglobulin-likereceptor 3DL1 (CD158 antigen-like family member E) KIR3DL1 CD158E 444(HLA-BW4-specific inhibitory NK cell receptor) (MHC class I NK cellreceptor) (Natural NKAT3 NKB1 killer-associated transcript 3) (NKAT-3)(p70 natural killer cell receptor clones CL-2/CL- 11) (p70 NK receptorCL-2/CL-11) (CD antigen CD158e) Q8N743 KI3L3_HUMAN Killer cellimmunoglobulin-like receptor 3DL3 (CD158 antigen-like family member Z)KIR3DL3 CD158Z 410 (Killer cell inhibitory receptor 1) (CD antigenCD158z) KIR3DL7 KIRC1 Q96J84 KIRR1_HUMAN Kin of IRRE-like protein 1 (Kinof irregular chiasm-like protein 1) (Nephrin-like protein 1) KIRRELKIRREL1 757 NEPH1 P10721 KIT_HUMAN Mast/stem cell growth factor receptorKit (SCFR) (EC 2.7.10.1) (Piebald trait protein) KIT SCFR 976 (PBT)(Proto-oncogene c-Kit) (Tyrosine-protein kinase Kit) (p145 c-kit) (v-kitHardy- Zuckerman 4 feline sarcoma viral oncogene homolog) (CD antigenCD117) Q86UK5 LBN_HUMAN Limbin (Ellis-van Creveld syndrome protein 2)(EVC2) EVC2 LBN 1308 P43627 KI2L2_HUMAN Killer cell immunoglobulin-likereceptor 2DL2 (CD158 antigen-like family member B1) KIR2DL2 CD158B1 348(MHC class I NK cell receptor) (Natural killer-associated transcript 6)(NKAT-6) (p58 NKAT6 natural killer cell receptor clone CL-43) (p58 NKreceptor CL-43) (CD antigen CD158b1) Q8N109 KI2LA_HUMAN Killer cellimmunoglobulin-like receptor 2DL5A (CD antigen CD158f1) KIR2DL5A CD158F375 CD158F1 KIR2DL5 P43631 KI2S2_HUMAN Killer cell immunoglobulin-likereceptor 2DS2 (CD158 antigen-like family member J) KIR2DS2 CD158J 304(MHC class I NK cell receptor) (NK receptor 183 Actl) (Naturalkiller-associated transcript NKAT5 5) (NKAT-5) (p58 natural killer cellreceptor clone CL-49) (p58 NK receptor CL-49) (CD antigen CD158j) P43630KI3L2_HUMAN Killer cell immunoglobulin-like receptor 3DL2 (CD158antigen-like family member K) KIR3DL2 CD158K 455 (MHC class I NK cellreceptor) (Natural killer-associated transcript 4) (NKAT-4) (p70 NKAT4natural killer cell receptor clone CL-5) (p70 NK receptor CL-5) (CDantigen CD158k) Q8TBQ9 KISHA_HUMAN Protein kish-A (Transmembrane protein167) (Transmembrane protein 167A) TMEM167A 72 TMEM167 Q96MU8 KREM1_HUMANKremen protein 1 (Dickkopf receptor) (Kringle domain-containingtransmembrane protein KREMEN1 473 1) (Kringle-containing protein markingthe eye and the nose) KREMEN KRM1 P11279 LAMP1_HUMAN Lysosome-associatedmembrane glycoprotein 1 (LAMP-1) (Lysosome-associated LAMP1 417 membraneprotein 1) (CD107 antigen-like family member A) (CD antigen CD107a)P13473 LAMP2_HUMAN Lysosome-associated membrane glycoprotein 2 (LAMP-2)(Lysosome-associated LAMP2 410 membrane protein 2) (CD107 antigen-likefamily member B) (CD antigen CD107b) P01130 LDLR_HUMAN Low-densitylipoprotein receptor (LDL receptor) LDLR 860 Q9UEF7 KLOT_HUMAN Klotho(EC 3.2.1.31) [Cleaved into: Klotho peptide] KL 1012 A6NM11 L37A2_HUMANLeucine-rich repeat-containing protein 37A2 LRRC37A2 1700 Q9UJQ1LAMP5_HUMAN Lysosome-associated membrane glycoprotein 5 (Brain anddendritic cell-associated LAMP5 C20orf103 280 LAMP) (Brain-associatedLAMP-like protein) (BAD-LAMP) (Lysosome-associated membrane protein 5)(LAMP-5) P19256 LFA3_HUMAN Lymphocyte function-associated antigen 3(Ag3) (Surface glycoprotein LFA-3) (CD CD58 LFA3 250 antigen CD58)Q8NCW0 KREM2_HUMAN Kremen protein 2 (Dickkopf receptor 2) (Kringledomain-containing transmembrane KREMEN2 KRM2 462 protein 2)(Kringle-containing protein marking the eye and the nose) A6NMS7L37A1_HUMAN Leucine-rich repeat-containing protein 37A LRRC37A 1700LRRC37A1 O60309 L37A3_HUMAN Leucine-rich repeat-containing protein 37A3LRRC37A3 1634 KIAA0563 P18627 LAG3_HUMAN Lymphocyte activation gene 3protein (LAG-3) (Protein FDC) (CD antigen CD223) LAG3 FDC 525 Q6UX15LAYN_HUMAN Layilin LAYN 382 UNQ208/PRO234 P48357 LEPR_HUMAN Leptinreceptor (LEP-R) (HuB219) (OB receptor) (OB-R) (CD antigen CD295) LEPRDB OBR 1165 Q8N149 LIRA2_HUMAN Leukocyte immunoglobulin-like receptorsubfamily A member 2 (CD85 antigen-like family LILRA2 ILT1 LIR7 483member H) (Immunoglobulin-like transcript 1) (ILT-1) (Leukocyteimmunoglobulin-like receptor 7) (LIR-7) (CD antigen CD85h) A6NI73LIRA5_HUMAN Leukocyte immunoglobulin-like receptor subfamily A member 5(CD85 antigen-like family LILRA5 ILT11 299 member F)(Immunoglobulin-like transcript 11) (ILT-11) (Leukocyteimmunoglobulin-like LILRB7 LIR9 receptor 9) (LIR-9) (CD antigen CD85f)Q8N423 LIRB2_HUMAN Leukocyte immunoglobulin-like receptor subfamily Bmember 2 (LIR-2) (Leukocyte LILRB2 ILT4 LIR2 598 immunoglobulin-likereceptor 2) (CD85 antigen-like family member D) (Immunoglobulin- MIR10like transcript 4) (ILT-4) (Monocyte/macrophage immunoglobulin-likereceptor 10) (MIR- 10) (CD antigen CD85d) P42702 LIFR_HUMAN Leukemiainhibitory factor receptor (LIF receptor) (LIF-R) (CD antigen CD118)LIFR 1097 Q6UY18 LIGO4_HUMAN Leucine-rich repeat and immunoglobulin-likedomain-containing nogo receptor-interacting LINGO4 LRRN6D 593 protein 4(Leucine-rich repeat neuronal protein 6D) UNQ9248/PRO34002 Q6PI73LIRA6_HUMAN Leukocyte immunoglobulin-like receptor subfamily A member 6(Immunoglobulin-like LILRA6 ILT8 481 transcript 8) (ILT-8) (LeukocyteIg-like receptor) O75022 LIRB3_HUMAN Leukocyte immunoglobulin-likereceptor subfamily B member 3 (LIR-3) (Leukocyte LILRB3 ILT5 LIR3 631immunoglobulin-like receptor 3) (CD85 antigen-like family member A)(Immunoglobulin- like transcript 5) (ILT-5) (Monocyte inhibitoryreceptor HL9) (CD antigen CD85a) P49257 LMAN1_HUMAN Protein ERGIC-53(ER-Golgi intermediate compartment 53 kDa protein) (Gp58) LMAN1 ERGIC53510 (Intracellular mannose-specific lectin MR60) (Lectinmannose-binding 1) F5F8D Q9UQV4 LAMP3_HUMAN Lysosome-associated membraneglycoprotein 3 (LAMP-3) (Lysosomal-associated LAMP3 DCLAMP 416 membraneprotein 3) (DC-lysosome-associated membrane glycoprotein) (DC LAMP)TSC403 (Protein TSC403) (CD antigen CD208) Q7L985 LIGO2_HUMANLeucine-rich repeat and immunoglobulin-like domain-containing nogoreceptor-interacting LINGO2 LERN3 606 protein 2 (Leucine-rich repeatneuronal protein 3) (Leucine-rich repeat neuronal protein LRRN6C 6C)UNQ9234/PRO31993 Q9H0V9 LMA2L_HUMAN VIP36-like protein (Lectinmannose-binding 2-like) (LMAN2-like protein) LMAN2L VIPL 348 PSEC0028UNQ368/PRO704 P09848 LPH_HUMAN Lactase-phlorizin hydrolase(Lactase-glycosylceramidase) [Includes: Lactase (EC LCT LPH 19273.2.1.108); Phlorizin hydrolase (EC 3.2.1.62)] Q96FE5 LIGO1_HUMANLeucine-rich repeat and immunoglobulin-like domain-containing nogoreceptor-interacting LINGO1 LERN1 620 protein 1 (Leucine-rich repeat andimmunoglobulin domain-containing protein 1) (Leucine- LRRN6A rich repeatneuronal protein 1) (Leucine-rich repeat neuronal protein 6A)UNQ201/PRO227 Q12907 LMAN2_HUMAN Vesicular integral-membrane proteinVIP36 (Glycoprotein GP36b) (Lectin mannose- LMAN2 C5orf8 356 binding 2)(Vesicular integral-membrane protein 36) (VIP36) Q9H756 LRC19_HUMANLeucine-rich repeat-containing protein 19 LRRC19 370 Q5VT99 LRC38_HUMANLeucine-rich repeat-containing protein 38 (BK channel auxiliary gammasubunit LRRC38) LRRC38 294 A6NDA9 LRIT2_HUMAN Leucine-rich repeat,immunoglobulin-like domain and transmembrane domain-containing LRIT2LRRC22 550 protein 2 (Leucine-rich repeat-containing protein 22) P16150LEUK_HUMAN Leukosialin (Galactoglycoprotein) (GALGP) (Leukocytesialoglycoprotein) (Sialophorin) SPN CD43 400 (CD antigen CD43) P0C6S8LIGO3_HUMAN Leucine-rich repeat and immunoglobulin-likedomain-containing nogo receptor-interacting LINGO3 LERN2 592 protein 3(Leucine-rich repeat neuronal protein 2) (Leucine-rich repeat neuronalprotein LRRN6B 6B) O75023 LIRB5_HUMAN Leukocyte immunoglobulin-likereceptor subfamily B member 5 (CD85 antigen-like family LILRB5 LIR8 590member C) (Leukocyte immunoglobulin-like receptor 8) (LIR-8) (CD antigenCD85c) Q9HAT1 LMA1L_HUMAN Protein ERGIC-53-like (ERGIC53-like protein)(Lectin mannose-binding 1-like) (LMAN1- LMAN1L ERGL 526 like protein)UNQ2784/PRO7174 O75197 LRP5_HUMAN Low-density lipoproteinreceptor-related protein 5 (LRP-5) LRP5 LR3 LRP7 1615 O75581 LRP6_HUMANLow-density lipoprotein receptor-related protein 6 (LRP-6) LRP6 1613Q9H3W5 LRRN3_HUMAN Leucine-rich repeat neuronal protein 3 (Neuronalleucine-rich repeat protein 3) (NLRR-3) LRRN3 Nbla10363 708UNQ194/PRO220 P59901 LIRA4_HUMAN Leukocyte immunoglobulin-like receptorsubfamily A member 4 (CD85 antigen-like family LILRA4 ILT7 499 member G)(Immunoglobulin-like transcript 7) (ILT-7) (CD antigen CD85g) Q8NHL6LIRB1_HUMAN Leukocyte immunoglobulin-like receptor subfamily B member 1(LIR-1) (Leukocyte LILRB1 ILT2 LIR1 650 immunoglobulin-like receptor 1)(CD85 antigen-like family member J) (Immunoglobulin- MIR7 liketranscript 2) (ILT-2) (Monocyte/macrophage immunoglobulin-like receptor7) (MIR-7) (CD antigen CD85j) Q96QE4 LR37B_HUMAN Leucine-richrepeat-containing protein 37B (C66 SLIT-like testicular protein) LRRC37B947 Q9HCJ2 LRC4C_HUMAN Leucine-rich repeat-containing protein 4C(Netrin-G1 ligand) (NGL-1) LRRC4C KIAA1580 640 NGL1 UNQ292/PRO331 Q9P2V4LRIT1_HUMAN Leucine-rich repeat, immunoglobulin-like domain andtransmembrane domain-containing LRIT1 LRRC21 PAL 623 protein 1(Leucine-rich repeat-containing protein 21) (Photoreceptor-associatedLRR superfamily protein) (Retina-specific protein PAL) P29376 LTK_HUMANLeukocyte tyrosine kinase receptor (EC 2.7.10.1) (Protein tyrosinekinase 1) LTK TYK1 864 Q9HBG7 LY9_HUMAN T-lymphocyte surface antigenLy-9 (Cell surface molecule Ly-9) (Lymphocyte antigen 9) LY9 CDABP0070655 (SLAM family member 3) (SLAMF3) (Signaling lymphocytic activationmolecule 3) (CD antigen CD229) P14151 LYAM1_HUMAN L-selectin (CD62antigen-like family member L) (Leukocyte adhesion molecule 1) (LAM-1)SELL LNHR LYAM1 372 (Leukocyte surface antigen Leu-8)(Leukocyte-endothelial cell adhesion molecule 1) (LECAM1) (Lymph nodehoming receptor) (TQ1) (gp90-MEL) (CD antigen CD62L) Q5SZI1 LRAD2_HUMANLow-density lipoprotein receptor class A domain-containing protein 2LDLRAD2 272 Q8TF66 LRC15_HUMAN Leucine-rich repeat-containing protein 15(Leucine-rich repeat protein induced by beta- LRRC15 LIB 581 amyloidhomolog) (hLib) Q2I0M4 LRC26_HUMAN Leucine-rich repeat-containingprotein 26 (BK channel auxiliary gamma subunit LRRC26) LRRC26 CAPC 334(Cytokeratin-associated protein in cancer) Q9P244 LRFN1_HUMANLeucine-rich repeat and fibronectin type III domain-containing protein 1(Synaptic LRFN1 KIAA1484 771 adhesion-like molecule 2) SALM2 Q9ULH4LRFN2_HUMAN Leucine-rich repeat and fibronectin type-IIIdomain-containing protein 2 (Synaptic LRFN2 KIAA1246 789 adhesion-likemolecule 1) SALM1 Q9BTN0 LRFN3_HUMAN Leucine-rich repeat and fibronectintype-III domain-containing protein 3 (Synaptic LRFN3 SALM4 628adhesion-like molecule 4) UNQ5865/PRO34192 Q6PJG9 LRFN4_HUMANLeucine-rich repeat and fibronectin type-III domain-containing protein 4LRFN4 SALM3 635 Q96NI6 LRFN5_HUMAN Leucine-rich repeat and fibronectintype-III domain-containing protein 5 LRFN5 C14orf146 719 SALM5 Q96JA1LRIG1_HUMAN Leucine-rich repeats and immunoglobulin-like domains protein1 (LIG-1) LRIG1 LIG1 1093 O94898 LRIG2_HUMAN Leucine-rich repeats andimmunoglobulin-like domains protein 2 (LIG-2) LRIG2 KIAA0806 1065 LIG2Q6UXM1 LRIG3_HUMAN Leucine-rich repeats and immunoglobulin-like domainsprotein 3 (LIG-3) LRIG3 LIG3 1119 UNQ287/PRO326/ PRO335 Q9HBW1LRRC4_HUMAN Leucine-rich repeat-containing protein 4 (Braintumor-associated protein BAG) LRRC4 BAG 653 (Nasopharyngealcarcinoma-associated gene 14 protein) (Netrin-G2 ligand) (NGL-2) NAG14UNQ554/PRO1111 Q6UXK5 LRRN1_HUMAN Leucine-rich repeat neuronal protein 1(Neuronal leucine-rich repeat protein 1) (NLRR-1) LRRN1 KIAA1497 716Nbla10449 UNQ693/PRO1338 Q86VH5 LRRT3_HUMAN Leucine-rich repeattransmembrane neuronal protein 3 LRRTM3 581 UNQ803/PRO1693 P16581LYAM2_HUMAN E-selectin (CD62 antigen-like family member E) (Endothelialleukocyte adhesion SELE ELAM1 610 molecule 1) (ELAM-1)(Leukocyte-endothelial cell adhesion molecule 2) (LECAM2) (CD antigenCD62E) P16109 LYAM3_HUMAN P-selectin (CD62 antigen-like family member P)(Granule membrane protein 140) (GMP- SELP GMRP GRMP 830 140)(Leukocyte-endothelial cell adhesion molecule 3) (LECAM3) (Plateletactivation dependent granule-external membrane protein) (PADGEM) (CDantigen CD62P) O75019 LIRA1_HUMAN Leukocyte immunoglobulin-like receptorsubfamily A member 1 (CD85 antigen-like family LILRA1 LIR6 489 member I)(Leukocyte immunoglobulin-like receptor 6) (LIR-6) (CD antigen CD85i)Q8NHJ6 LIRB4_HUMAN Leukocyte immunoglobulin-like receptor subfamily Bmember 4 (CD85 antigen-like family LILRB4 ILT3 LIR5 448 member K)(Immunoglobulin-like transcript 3) (ILT-3) (Leukocyteimmunoglobulin-like receptor 5) (LIR-5) (Monocyte inhibitory receptorHM18) (CD antigen CD85k) Q6ZMQ8 LMTK1_HUMAN Serine/threonine-proteinkinase LMTK1 (EC 2.7.11.1) (Apoptosis-associated tyrosine AATK AATYK1374 kinase) (AATYK) (Brain apoptosis-associated tyrosine kinase)(CDK5-binding protein) KIAA0641 LMR1 (Lemur tyrosine kinase 1)(p35-binding protein) (p35BP) LMTK1 Q8N386 LRC25_HUMAN Leucine-richrepeat-containing protein 25 (Monocyte and plasmacytoid-activatedprotein) LRRC25 MAPA 305 UNQ6169/PRO20174 Q8ND94 LRN4L_HUMAN LRRN4C-terminal-like protein LRRN4CL 238 UNQ728/PRO1410 Q86VZ4 LRP11_HUMANLow-density lipoprotein receptor-related protein 11 (LRP-11) LRP11 500Q07954 LRP1_HUMAN Prolow-density lipoprotein receptor-related protein 1(LRP-1) (Alpha-2-macroglobulin LRP1 A2MR APR 4544 receptor) (A2MR)(Apolipoprotein E receptor) (APOER) (CD antigen CD91) [Cleaved into:Low-density lipoprotein receptor-related protein 1 85 kDa subunit(LRP-85); Low-density lipoprotein receptor-related protein 1 515 kDasubunit (LRP-515); Low-density lipoprotein receptor-related protein 1intracellular domain (LRPICD)] O75074 LRP3_HUMAN Low-density lipoproteinreceptor-related protein 3 (LRP-3) (105 kDa low-density LRP3 770lipoprotein receptor-related protein) (hLRp105) O75096 LRP4_HUMANLow-density lipoprotein receptor-related protein 4 (LRP-4) (Multipleepidermal growth LRP4 KIAA0816 1905 factor-like domains 7) LRP10 MEGF7Q14114 LRP8_HUMAN Low-density lipoprotein receptor-related protein 8(LRP-8) (Apolipoprotein E receptor 2) LRP8 APOER2 963 O43300 LRRT2_HUMANLeucine-rich repeat transmembrane neuronal protein 2 (Leucine-richrepeat neuronal 2 LRRTM2 KIAA0416 516 protein) LRRN2 Q9HBL6 LRTM1_HUMANLeucine-rich repeat and transmembrane domain-containing protein 1 LRTM1HT017 345 Q7Z4F1 LRP10_HUMAN Low-density lipoprotein receptor-relatedprotein 10 (LRP-10) LRP10 MSTP087 713 SP220 UNQ389/PRO724 Q8N967LRTM2_HUMAN Leucine-rich repeat and transmembrane domain-containingprotein 2 LRTM2 370 Q9Y561 LRP12_HUMAN Low-density lipoproteinreceptor-related protein 12 (LRP-12) (Suppressor of LRP12 ST7 859tumorigenicity 7 protein) P98164 LRP2_HUMAN Low-density lipoproteinreceptor-related protein 2 (LRP-2) (Glycoprotein 330) (gp330) LRP2 4655(Megalin) Q9H8J5 MANS1_HUMAN MANSC domain-containing protein 1 (Loss ofheterozygosity 12 chromosomal region 3 MANSC1 431 protein) LOH12CR3UNQ316/PRO361 Q86YD5 LRAD3_HUMAN Low-density lipoprotein receptor classA domain-containing protein 3 LDLRAD3 345 Q14392 LRC32_HUMANLeucine-rich repeat-containing protein 32 (Garpin) (Glycoprotein Arepetitions LRRC32 D11S833E 662 predominant) (GARP) GARP Q9NZR2LRP1B_HUMAN Low-density lipoprotein receptor-related protein 1B (LRP-1B)(Low-density lipoprotein LRP1B LRPDIT 4599 receptor-relatedprotein-deleted in tumor) (LRP-DIT) O75325 LRRN2_HUMAN Leucine-richrepeat neuronal protein 2 (Glioma amplified on chromosome 1 protein)LRRN2 GAC1 713 (Leucine-rich repeat neuronal protein 5) LRRN5UNQ256/PRO293 Q8WUT4 LRRN4_HUMAN Leucine-rich repeat neuronal protein 4(Neuronal leucine-rich repeat protein 4) (NLRR-4) LRRN4 C20orf75 740Q86UE6 LRRT1_HUMAN Leucine-rich repeat transmembrane neuronal protein 1LRRTM1 522 UNQ675/PRO1309 A6NHS7 MANS4_HUMAN MANSC domain-containingprotein 4 MANSC4 340 P15529 MCP_HUMAN Membrane cofactor protein (TLX)(Trophoblast leukocyte common antigen) (CD antigen CD46 MCP MIC10 392CD46) Q86VH4 LRRT4_HUMAN Leucine-rich repeat transmembrane neuronalprotein 4 LRRTM4 590 UNQ3075/PRO9907 Q13477 MADCA_HUMAN Mucosaladdressin cell adhesion molecule 1 (MAdCAM-1) (hMAdCAM-1) MADCAM1 382Q5SQ64 LY66F_HUMAN Lymphocyte antigen 6 complex locus protein G6f LY6G6FC6orf21 297 G6F LY6G6D NG32 O60449 LY75_HUMAN Lymphocyte antigen 75(Ly-75) (C-type lectin domain family 13 member B) (DEC-205) LY75 CD2051722 (gp200-MR6) (CD antigen CD205) CLEC13B Q9Y5Y7 LYVE1_HUMAN Lymphaticvessel endothelial hyaluronic acid receptor 1 (LYVE-1) (Cell surfaceretention LYVE1 CRSBP1 322 sequence-binding protein 1) (CRSBP-1)(Extracellular link domain-containing protein 1) HAR XLKD1 (Hyaluronicacid receptor) UNQ230/PRO263 P20916 MAG_HUMAN Myelin-associatedglycoprotein (Siglec-4a) MAG GMA 626 Q16820 MEP1B_HUMAN Meprin A subunitbeta (EC 3.4.24.63) (Endopeptidase-2) (Meprin B) (N-benzoyl-L-tyrosyl-MEP1B 701 P-amino-benzoic acid hydrolase subunit beta) (PABA peptidehydrolase) (PPH beta) Q9H9K5 MER34_HUMAN Endogenous retrovirus groupMER34 member 1 Env polyprotein (HERV-MER_4q12 ERVMER34-1 563 provirusancestral Env polyprotein) LP9056 Q14703 MBTP1_HUMAN Membrane-boundtranscription factor site-1 protease (EC 3.4.21.112) (EndopeptidaseMBTPS1 KIAA0091 1052 S1P) (Subtilisin/kexin-isozyme 1) (SKI-1) S1P SKI1Q12866 MERTK_HUMAN Tyrosine-protein kinase Mer (EC 2.7.10.1)(Proto-oncogene c-Mer) (Receptor tyrosine MERTK MER 999 kinase MerTK)Q7Z7M0 MEGF8_HUMAN Multiple epidermal growth factor-like domains protein8 (Multiple EGF-like domains MEGF8 C19orf49 2845 protein 8) (Epidermalgrowth factor-like protein 4) (EGF-like protein 4) EGFL4 KIAA0817 P55082MFAP3_HUMAN Microfibril-associated glycoprotein 3 MFAP3 362 Q96KG7MEG10_HUMAN Multiple epidermal growth factor-like domains protein 10(Multiple EGF-like domains MEGF10 KIAA1780 1140 protein 10) A6BM72MEG11_HUMAN Multiple epidermal growth factor-like domains protein 11(Multiple EGF-like domains MEGF11 KIAA1781 1044 protein 11)UNQ1949/PRO4432 Q16819 MEP1A_HUMAN Meprin A subunit alpha (EC 3.4.24.18)(Endopeptidase-2) (N-benzoyl-L-tyrosyl-P-amino- MEP1A 746 benzoic acidhydrolase subunit alpha) (PABA peptide hydrolase) (PPH alpha) P51512MMP16_HUMAN Matrix metalloproteinase-16 (MMP-16) (EC 3.4.24.—) (MMP-X2)(Membrane-type matrix MMP16 MMPX2 607 metalloproteinase 3) (MT-MMP 3)(MTMMP3) (Membrane-type-3 matrix metalloproteinase) (MT3-MMP) (MT3MMP)Q9H1U4 MEGF9_HUMAN Multiple epidermal growth factor-like domains protein9 (Multiple EGF-like domains MEGF9 EGFL5 602 protein 9) (Epidermalgrowth factor-like protein 5) (EGF-like protein 5) KIAA0818UNQ671/PRO1305 Q5JRA6 MIA3_HUMAN Melanoma inhibitory activity protein 3(C219-reactive peptide) (D320) (Transport and MIA3 KIAA0268 1907 Golgiorganization protein 1) TANGO TANGO1 UNQ6077/PRO20088 P51511 MMP15_HUMANMatrix metalloproteinase-15 (MMP-15) (EC 3.4.24.—) (Membrane-type matrixMMP15 669 metalloproteinase 2) (MT-MMP 2) (MTMMP2) (Membrane-type-2matrix metalloproteinase) (MT2-MMP) (MT2MMP) (SMCP-2) O75121 MFA3L_HUMANMicrofi brillar-associated protein 3-like (Testis development proteinNYD-SP9) MFAP3L KIAA0626 409 HSD-39 HSD39 P08581 MET_HUMAN Hepatocytegrowth factor receptor (HGF receptor) (EC 2.7.10.1) (HGF/SF receptor)MET 1390 (Proto-oncogene c-Met) (Scatter factor receptor) (SF receptor)(Tyrosine-protein kinase Met) Q29983 MICA_HUMAN MHC class Ipolypeptide-related sequence A (MIC-A) MICA PERB11.1 383 Q8TD46MO2R1_HUMAN Cell surface glycoprotein CD200 receptor 1 (CD200 cellsurface glycoprotein receptor) CD200R1 CD200R 325 (Cell surfaceglycoprotein OX2 receptor 1) CRTR2 MOX2R OX2R UNQ2522/PRO6015 Q29980MICB_HUMAN MHC class I polypeptide-related sequence B (MIC-B) MICBPERB11.2 383 P50281 MMP14_HUMAN Matrix metalloproteinase-14 (MMP-14) (EC3.4.24.80) (MMP-X1) (Membrane-type matrix MMP14 582 metalloproteinase 1)(MT-MMP 1) (MTMMP1) (Membrane-type-1 matrix metalloproteinase) (MT1-MMP)(MT1MMP) Q2M385 MPEG1_HUMAN Macrophage-expressed gene 1 protein(Macrophage gene 1 protein) (Mpg-1) MPEG1 716 Q7Z6M3 MILR1_HUMANAllergin-1 (Allergy inhibitory receptor 1) (Mast cell antigen 32)(MCA-32) (Mast cell MILR1 C17orf60 343 immunoglobulin-like receptor 1)MCA32 P20645 MPRD_HUMAN Cation-dependent mannose-6-phosphate receptor(CD Man-6-P receptor) (CD-MPR) (46 M6PR MPR46 277 kDa mannose6-phosphate receptor) (MPR 46) MPRD P11717 MPRI_HUMAN Cation-independentmannose-6-phosphate receptor (CI Man-6-P receptor) (CI-MPR) IGF2R MPRI2491 (M6PR) (300 kDa mannose 6-phosphate receptor) (MPR 300)(Insulin-like growth factor 2 receptor) (Insulin-like growth factor IIreceptor) (IGF-II receptor) (M6P/IGF2 receptor) (M6P/IGF2R) (CD antigenCD222) Q14165 MLEC_HUMAN Malectin MLEC KIAA0152 292 Q9Y5R2 MMP24_HUMANMatrix metalloproteinase-24 (MMP-24) (EC 3.4.24.—) (Membrane-type matrixMMP24 MT5MMP 645 metalloproteinase 5) (MT-MMP 5) (MTMMP5)(Membrane-type-5 matrix metalloproteinase) (MT5-MMP) (MT5MMP) [Cleavedinto: Processed matrix metalloproteinase-24] Q16653 MOG_HUMANMyelin-oligodendrocyte glycoprotein MOG 247 Q6UWV2 MPZL3_HUMAN Myelinprotein zero-like protein 3 MPZL3 235 UNQ2966/PRO7425 Q6UVY6 MOXD1_HUMANDBH-like monooxygenase protein 1 (EC 1.14.17.—) (Monooxygenase X) MOXD1MOX 613 UNQ2493/PRO5780 Q6Q8B3 MO2R2_HUMAN Cell surface glycoproteinCD200 receptor 2 (CD200 cell surface glycoprotein receptor-like CD200R1L271 2) (CD200 receptor-like 2) (HuCD200R2) (CD200 cell surfaceglycoprotein receptor-like CD200R2 a) (CD200RLa) (Cell surfaceglycoprotein CD200 receptor 1-like) (Cell surface glycoprotein OX2receptor 2) O60487 MPZL2_HUMAN Myelin protein zero-like protein 2(Epithelial V-like antigen 1) MPZL2 EVA EVA1 215 UNQ606/PRO1192 Q96KJ4MSLNL_HUMAN Mesothelin-like protein(Pre-pro-megakaryocyte-potentiating-factor-like) MSLNL C16orf37 702 MPFLP43121 MUC18_HUMAN Cell surface glycoprotein MUC18 (Cell surfaceglycoprotein P1H12) (Melanoma cell MCAM MUC18 646 adhesion molecule)(Melanoma-associated antigen A32) (Melanoma-associated antigen MUC18)(S-endo 1 endothelial-associated antigen) (CD antigen CD146) P15941MUC1_HUMAN Mucin-1 (MUC-1) (Breast carcinoma-associated antigen DF3)(Cancer antigen 15-3) (CA MUC1 PUM 1255 15-3) (Carcinoma-associatedmucin) (Episialin) (H23AG) (Krebs von den Lungen-6) (KL- 6) (PEMT)(Peanut-reactive urinary mucin) (PUM) (Polymorphic epithelial mucin)(PEM) (Tumor-associated epithelial membrane antigen) (EMA)(Tumor-associated mucin) (CD antigen CD227) [Cleaved into: Mucin-1subunit alpha (MUC1-NT) (MUC1-alpha); Mucin-1 subunit beta (MUC1-beta)(MUC1-CT)] O95297 MPZL1_HUMAN Myelin protein zero-like protein 1(Protein zero-related) MPZL1 PZR 269 UNQ849/PRO1787 P22897 MRC1_HUMANMacrophage mannose receptor 1 (MMR) (C-type lectin domain family 13member D) (C- MRC1 CLEC13D 1456 type lectin domain family 13 memberD-like) (Human mannose receptor) (hMR) CLEC13DL (Macrophage mannosereceptor 1-like protein 1) (CD antigen CD206) MRC1L1 Q9UBG0 MRC2_HUMANC-type mannose receptor 2 (C-type lectin domain family 13 member E)(Endocytic MRC2 CLEC13E 1479 receptor 180) (Macrophage mannose receptor2) (Urokinase-type plasminogen activator ENDO180 receptor-associatedprotein) (UPAR-associated protein) (Urokinase receptor-associatedKIAA0709 UPARAP protein) (CD antigen CD280) Q9UKN1 MUC12_HUMAN Mucin-12(MUC-12) (Mucin-11) (MUC-11) MUC12 MUC11 5478 Q8N387 MUC15_HUMANMucin-15 (MUC-15) MUC15 334 UNQ750/PRO1481 Q8WXI7 MUC16_HUMAN Mucin-16(MUC-16) (Ovarian cancer-related tumor marker CA125) (CA-125) (OvarianMUC16 CA125 14507 carcinoma antigen CA125) Q5SSG8 MUC21_HUMAN Mucin-21(MUC-21) (Epiglycanin) MUC21 C6orf205 566 UNQ697/PRO1342 Q9H3R2MUC13_HUMAN Mucin-13 (MUC-13) (Down-regulated in colon cancer 1) MUC13DRCC1 512 RECC UNQ6194/PRO20221 O15146 MUSK_HUMAN Muscle, skeletalreceptor tyrosine-protein kinase (EC 2.7.10.1) (Muscle-specifictyrosine- MUSK 869 protein kinase receptor) (MuSK) (Muscle-specifickinase receptor) Q13505 MTX1_HUMAN Metaxin-1 (Mitochondrial outermembrane import complex protein 1) MTX1 MTX MTXN 466 Q9ULC0 MUCEN_HUMANEndomucin (Endomucin-2) (Gastric cancer antigen Ga34) (Mucin-14)(MUC-14) EMCN EMCN2 261 MUC14 Q04900 MUC24_HUMAN Sialomucin core protein24 (MUC-24) (Endolyn) (Multi-glycosylated core protein 24) CD164 197(MGC-24) (MGC-24v) (CD antigen CD164) P25189 MYP0_HUMAN Myelin proteinP0 (Myelin peripheral protein) (MPP) (Myelin protein zero) MPZ 248Q9BRK3 MXRA8_HUMAN Matrix-remodeling-associated protein 8 (Limitrin)MXRA8 442 Q9UK23 NAGPA_HUMAN N-acetylglucosamine-1-phosphodiesteralpha-N-acetylglucosaminidase (EC 3.1.4.45) NAGPA 515 (Mannose6-phosphate-uncovering enzyme) (Phosphodiester alpha-GlcNAcase) O15394NCAM2_HUMAN Neural cell adhesion molecule 2 (N-CAM-2) (NCAM-2) NCAM2NCAM21 837 O76036 NCTR1_HUMAN Natural cytotoxicity triggering receptor 1(Lymphocyte antigen 94 homolog) (NK cell- NCR1 LY94 304 activatingreceptor) (Natural killer cell p46-related protein) (NK-p46) (NKp46)(hNKp46) (CD antigen CD335) Q8NC67 NETO2_HUMAN Neuropilin andtolloid-like protein 2 (Brain-specific transmembrane protein containing2 NETO2 BTCL2 525 CUB and 1 LDL-receptor class A domains protein 2)UNQ1926/PRO4401 Q8TD07 N2DL4_HUMAN NKG2D ligand 4 (N2DL-4) (NKG2DL4)(Lymphocyte effector toxicity activation ligand) RAET1E LETAL 263(RAE-1-like transcript 4) (RL-4) (Retinoic acid early transcript 1E)N2DL4 ULBP4 UNQ1867/PRO4303 O14931 NCTR3_HUMAN Natural cytotoxicitytriggering receptor 3 (Activating natural killer receptor p30) (NaturalNCR3 1C7 LY117 201 killer cell p30-related protein) (NK-p30) (NKp30) (CDantigen CD337) Q8TDF5 NETO1_HUMAN Neuropilin and tolloid-like protein 1(Brain-specific transmembrane protein containing 2 NETO1 BTCL1 533 CUBand 1 LDL-receptor class A domains protein 1) Q92542 NICA_HUMANNicastrin NCSTN KIAA0253 709 UNQ1874/PRO4317 P13591 NCAM1_HUMAN Neuralcell adhesion molecule 1 (N-CAM-1) (NCAM-1) (CD antigen CD56) NCAM1 NCAM858 Q5T1S8 NCMAP_HUMAN Noncompact myelin-associated protein (Myelinprotein of 11 kDa) (MP11) NCMAP C1orf130 102 O95944 NCTR2_HUMAN Naturalcytotoxicity triggering receptor 2 (Lymphocyte antigen 95 homolog) (NKcell- NCR2 LY95 276 activating receptor) (Natural killer cellp44-related protein) (NK-p44) (NKp44) (CD antigen CD336) Q15223NECT1_HUMAN Nectin-1 (Herpes virus entry mediator C) (Herpesvirus entrymediator C) (HveC) NECTIN1 HVEC 517 (Herpesvirus Ig-like receptor)(HIgR) (Nectin cell adhesion molecule 1) (Poliovirus PRR1 PVRL1receptor-related protein 1) (CD antigen CD111) Q92859 NEO1_HUMANNeogenin (Immunoglobulin superfamily DCC subclass member 2) NEO1 IGDCC21461 NGN O00533 NCHL1_HUMAN Neural cell adhesion molecule L1-likeprotein (Close homolog of L1) [Cleaved into: CHL1 CALL 1208 Processedneural cell adhesion molecule L1-like protein] Q8N2Q7 NLGN1_HUMANNeuroligin-1 NLGN1 KIAA1070 840 Q8N0W4 NLGNX_HUMAN Neuroligin-4,X-linked (Neuroligin X) (HNLX) NLGN4X KIAA1260 816 NLGN4 UNQ365/PRO701O60500 NPHN_HUMAN Nephrin (Renal glomerulus-specific cell adhesionreceptor) NPHS1 NPHN 1241 Q96NY8 NECT4_HUMAN Nectin-4 (Ig superfamilyreceptor LNIR) (Nectin cell adhesion molecule 4) (Poliovirus NECTIN4LNIR 510 receptor-related protein 4) [Cleaved into: Processed poliovirusreceptor-related protein 4] PRR4 PVRL4 Q8NET5 NFAM1_HUMAN NFATactivation molecule 1 (Calcineurin/NFAT-activating ITAM-containingprotein) NFAM1 CNAIP 270 (NFAT-activating protein with ITAM motif 1)O94856 NFASC_HUMAN Neurofascin NFASC KIAA0756 1347 Q9UM47 NOTC3_HUMANNeurogenic locus notch homolog protein 3 (Notch 3) [Cleaved into: Notch3 extracellular NOTCH3 2321 truncation; Notch 3 intracellular domain]O14511 NRG2_HUMAN Pro-neuregulin-2, membrane-bound isoform (Pro-NRG2)[Cleaved into: Neuregulin-2 NRG2 NTAK 850 (NRG-2) (Divergent ofneuregulin-1) (DON-1) (Neural- and thymus-derived activator for ERBBkinases) (NTAK)] Q02297 NRG1_HUMAN Pro-neuregulin-1, membrane-boundisoform (Pro-NRG1) [Cleaved into: Neuregulin-1 NRG1 GGF HGL 640(Acetylcholine receptor-inducing activity) (ARIA) (Breast cancer celldifferentiation factor HRGA NDF SMDF p45) (Glial growth factor)(Heregulin) (HRG) (Neu differentiation factor) (Sensory and motorneuron-derived factor)] Q9Y4C0 NRX3A_HUMAN Neurexin-3 (NeurexinIII-alpha) (Neurexin-3-alpha) NRXN3 C14orf60 1643 KIAA0743 Q92692NECT2_HUMAN Nectin-2 (Herpes virus entry mediator B) (Herpesvirus entrymediator B) (HveB) (Nectin NECTIN2 HVEB 538 cell adhesion molecule 2)(Poliovirus receptor-related protein 2) (CD antigen CD112) PRR2 PVRL2Q8NFZ4 NLGN2_HUMAN Neuroligin-2 NLGN2 KIAA1366 835 Q8NFZ3 NLGNY_HUMANNeuroligin-4, Y-linked (Neuroligin Y) NLGN4Y KIAA0951 816 Q15155NOMO1_HUMAN Nodal modulator 1 (pM5 protein) NOMO1 PM5 1222 P69849NOMO3_HUMAN Nodal modulator 3 (pM5 protein 3) NOMO3 1222 Q9NZ94NLGN3_HUMAN Neuroligin-3 (Gliotactin homolog) NLGN3 KIAA1480 848 NL3P46531 NOTC1_HUMAN Neurogenic locus notch homolog protein 1 (Notch 1)(hN1) (Translocation-associated NOTCH1 TAN1 2555 notch protein TAN-1)[Cleaved into: Notch 1 extracellular truncation (NEXT); Notch 1intracellular domain (NICD)] Q04721 NOTC2_HUMAN Neurogenic locus notchhomolog protein 2 (Notch 2) (hN2) [Cleaved into: Notch 2 NOTCH2 2471extracellular truncation (N2ECD); Notch 2 intracellular domain (N2ICD)]Q92823 NRCAM_HUMAN Neuronal cell adhesion molecule (Nr-CAM) (Neuronalsurface protein Bravo) (hBravo) NRCAM KIAA0343 1304 (NgCAM-related celladhesion molecule) (Ng-CAM-related) O60462 NRP2_HUMAN Neuropilin-2(Vascular endothelial cell growth factor 165 receptor 2) NRP2 VEGF165R2931 Q9Y639 NPTN_HUMAN Neuroplastin (Stromal cell-derived receptor 1)(SDR-1) NPTN SDFR1 398 SDR1 Q68D85 NR3L1_HUMAN Natural cytotoxicitytriggering receptor 3 ligand 1 (B7 homolog 6) (B7-H6) NCR3LG1 B7H6 454O14786 NRP1_HUMAN Neuropilin-1 (Vascular endothelial cell growth factor165 receptor) (CD antigen CD304) NRP1 NRP 923 VEGF165R P56975 NRG3_HUMANPro-neuregulin-3, membrane-bound isoform (Pro-NRG3) [Cleaved into:Neuregulin-3 NRG3 720 (NRG-3)] Q86YC3 NRROS_HUMAN Negative regulator ofreactive oxygen species (Leucine-rich repeat-containing protein 33)NRROS LRRC33 692 UNQ3030/PRO9833 P58400 NRX1B_HUMAN Neurexin-1-beta(Neurexin 1-beta) NRXN1 442 Q9HDB5 NRX3B_HUMAN Neurexin-3-beta (NeurexinIII-beta) [Cleaved into: Neurexin-3-beta, soluble form; NRXN3 KIAA0743637 Neurexin-3-beta, C-terminal fragment (NRXN3-CTF)] Q16620 NTRK2_HUMANBDNF/NT-3 growth factors receptor (EC 2.7.10.1) (GP145-TrkB) (Trk-B)(Neurotrophic NTRK2 TRKB 822 tyrosine kinase receptor type 2) (TrkBtyrosine kinase) (Tropomyosin-related kinase B) Q16288 NTRK3_HUMAN NT-3growth factor receptor (EC 2.7.10.1) (GP145-TrkC) (Trk-C) (Neurotrophictyrosine NTRK3 TRKC 839 kinase receptor type 3) (TrkC tyrosine kinase)Q99466 NOTC4_HUMAN Neurogenic locus notch homolog protein 4 (Notch 4)(hNotch4) [Cleaved into: Notch 4 NOTCH4 INT3 2003 extracellulartruncation; Notch 4 intracellular domain] Q8WWG1 NRG4_HUMANPro-neuregulin-4, membrane-bound isoform (Pro-NRG4) [Cleaved into:Neuregulin-4 NRG4 115 (NRG-4)] Q9P2S2 NRX2A_HUMAN Neurexin-2 (NeurexinII-alpha) (Neurexin-2-alpha) NRXN2 KIAA0921 1712 Q9ULB1 NRX1A_HUMANNeurexin-1 (Neurexin I-alpha) (Neurexin-1-alpha) NRXN1 KIAA0578 1477P58401 NRX2B_HUMAN Neurexin-2-beta (Neurexin II-beta) NRXN2 666 P04629NTRK1_HUMAN High affinity nerve growth factor receptor (EC 2.7.10.1)(Neurotrophic tyrosine kinase NTRK1 MTC TRK 796 receptor type 1)(TRK1-transforming tyrosine kinase protein) (Tropomyosin-related kinaseTRKA A) (Tyrosine kinase receptor) (Tyrosine kinase receptor A) (Trk-A)(gp140trk) (p140-TrkA) Q96PE5 OPALI_HUMAN Opalin (Oligodendrocyticmyelin paranodal and inner loop protein) (Transmembrane OPALIN HTMP10141 protein 10) TMEM10 P41217 OX2G_HUMAN OX-2 membrane glycoprotein (CDantigen CD200) CD200 MOX1 278 MOX2 My033 Q8NBR0 P5I13_HUMAN Tumorprotein p53-inducible protein 13 (Damage-stimulated cytoplasmicprotein 1) TP53I13 DSCP1 393 Q99650 OSMR_HUMAN Oncostatin-M-specificreceptor subunit beta (Interleukin-31 receptor subunit beta) (IL-31 OSMROSMRB 979 receptor subunit beta) (IL-31R subunit beta) (IL-31R-beta)(IL-31RB) Q8IYS5 OSCAR_HUMAN Osteoclast-associated immunoglobulin-likereceptor (Osteoclast-associated receptor) OSCAR 282 (hOSCAR) (Polymericimmunoglobulin receptor 3) (PIgR-3) (PIgR3) (Poly-Ig receptor 3) P39656OST48_HUMAN Dolichyl-diphosphooligosaccharide--proteinglycosyltransferase 48 kDa subunit (DDOST DDOST KIAA0115 456 48 kDasubunit) (Oligosaccharyl transferase 48 kDa subunit) (EC 2.4.99.18)OST48 OK/SW- cl.45 Q86WC4 OSTM1_HUMAN Osteopetrosis-associatedtransmembrane protein 1 (Chloride channel 7 beta subunit) OSTM1 GL 334HSPC019 UNQ6098/PRO21201 Q9BZA7 PC11X_HUMAN Protocadherin-11 X-linked(Protocadherin-11) (Protocadherin on the X chromosome) PCDH11X 1347(PCDH-X) (Protocadherin-S) KIAA1326 PCDH11 PCDHX Q9P2E7 PCD10_HUMANProtocadherin-10 PCDH10 KIAA1400 1040 Q96QU1 PCD15_HUMANProtocadherin-15 PCDH15 USH1F 1955 Q8N6Y1 PCD20_HUMAN Protocadherin-20(Protocadherin-13) PCDH20 PCDH13 951 Q9UN67 PCDBA_HUMAN Protocadherinbeta-10 (PCDH-beta-10) PCDHB10 800 UNQ1906/PRO4352 Q9Y5E8 PCDBF_HUMANProtocadherin beta-15 (PCDH-beta-15) PCDHB15 787 Q9Y5I4 PCDC2_HUMANProtocadherin alpha-C2 (PCDH-alpha-C2) PCDHAC2 1007 Q9Y5H0 PCDG3_HUMANProtocadherin gamma-A3 (PCDH-gamma-A3) PCDHGA3 932 Q9Y5G8 PCDG5_HUMANProtocadherin gamma-A5 (PCDH-gamma-A5) PCDHGA5 931 Q9Y5G6 PCDG7_HUMANProtocadherin gamma-A7 (PCDH-gamma-A7) PCDHGA7 932 Q9Y5G1 PCDGF_HUMANProtocadherin gamma-B3 (PCDH-gamma-B3) PCDHGB3 929 Q96FE7 P3IP1_HUMANPhosphoinositide-3-kinase-interacting protein 1 (Kringledomain-containing protein HGFL) PIK3IP1 HGFL 263 Q9HCL0 PCD18_HUMANProtocadherin-18 PCDH18 KIAA1562 1135 Q9Y5H7 PCDA5_HUMAN Protocadherinalpha-5 (PCDH-alpha-5) PCDHA5 CNRS6 936 Q9Y5I1 PCDAB_HUMAN Protocadherinalpha-11 (PCDH-alpha-11) PCDHA11 CNRS7 949 Q9Y5E7 PCDB2_HUMANProtocadherin beta-2 (PCDH-beta-2) PCDHB2 798 Q9Y5E5 PCDB4_HUMANProtocadherin beta-4 (PCDH-beta-4) PCDHB4 795 Q9HC56 PCDH9_HUMANProtocadherin-9 PCDH9 1237 Q92824 PCSK5_HUMAN Proprotein convertasesubtilisin/kexin type 5 (EC 3.4.21.—) (Proprotein convertase 5) PCSK5PC5 PC6 1860 (PC5) (Proprotein convertase 6) (PC6) (hPC6)(Subtilisin/kexin-like protease PC5) Q96JQ0 PCD16_HUMAN Protocadherin-16(Cadherin-19) (Cadherin-25) (Fibroblast cadherin-1) (Protein dachsousDCHS1 CDH19 3298 homolog 1) CDH25 FIB1 KIAA1773 PCDH16 Q9Y5I0PCDAD_HUMAN Protocadherin alpha-13 (PCDH-alpha-13) PCDHA13 CNRS5 950Q9Y5E6 PCDB3_HUMAN Protocadherin beta-3 (PCDH-beta-3) PCDHB3 796 Q9Y5E3PCDB6_HUMAN Protocadherin beta-6 (PCDH-beta-6) PCDHB6 794 Q9Y5F1PCDBC_HUMAN Protocadherin beta-12 (PCDH-beta-12) PCDHB12 795 Q9Y5G7PCDG6_HUMAN Protocadherin gamma-A6 (PCDH-gamma-A6) PCDHGA6 932 Q9Y5G5PCDG8_HUMAN Protocadherin gamma-A8 (PCDH-gamma-A8) PCDHGA8 932 KIAA0327Q9Y5H3 PCDGA_HUMAN Protocadherin gamma-A10 (PCDH-gamma-A10) PCDHGA10 936Q9Y5H2 PCDGB_HUMAN Protocadherin gamma-A11 (PCDH-gamma-A11) PCDHGA11 935Q9Y5F6 PCDGM_HUMAN Protocadherin gamma-C5 (PCDH-gamma-C5) PCDHGC5 944Q08174 PCDH1_HUMAN Protocadherin-1 (Cadherin-like protein 1)(Protocadherin-42) (PC42) PCDH1 1060 O95206 PCDH8_HUMAN Protocadherin-8(Arcadlin) PCDH8 1070 Q9NZQ7 PD1L1_HUMAN Programmed cell death 1 ligand1 (PD-L1) (PDCD1 ligand 1) (Programmed death ligand CD274 B7H1 290 1)(B7 homolog 1) (B7-H1) (CD antigen CD274) PDCD1L1 PDCD1LG1 PDL1 Q6UWI2PARM1_HUMAN Prostate androgen-regulated mucin-like protein 1 (PARM-1)PARM1 310 UNQ1879/PRO4322 Q9Y5I3 PCDA1_HUMAN Protocadherin alpha-1(PCDH-alpha-1) PCDHA1 950 Q9Y5H8 PCDA3_HUMAN Protocadherin alpha-3(PCDH-alpha-3) PCDHA3 950 Q9UN74 PCDA4_HUMAN Protocadherin alpha-4(PCDH-alpha-4) PCDHA4 947 Q86YL7 PDPN_HUMAN Podoplanin (Aggrus)(Glycoprotein 36) (Gp36) (PA2.26 antigen) (T1-alpha) (T1A) PDPN GP36 162PSEC0003 PSEC0025 P07202 PERT_HUMAN Thyroid peroxidase (TPO) (EC1.11.1.8) TPO 933 Q9BZA8 PC11Y_HUMAN Protocadherin-11 Y-linked(Protocadherin-11) (Protocadherin on the Y chromosome) PCDH11Y PCDH111340 (PCDH-Y) (Protocadherin prostate cancer) (Protocadherin-PC)(Protocadherin-22) PCDH22 PCDHY O14917 PCD17_HUMAN Protocadherin-17(Protocadherin-68) PCDH17 PCDH68 1159 PCH68 Q8TAB3 PCD19_HUMANProtocadherin-19 PCDH19 KIAA1313 1148 Q9UN73 PCDA6_HUMAN Protocadherinalpha-6 (PCDH-alpha-6) PCDHA6 CNRS2 950 Q9Y5I2 PCDAA_HUMAN Protocadherinalpha-10 (PCDH-alpha-10) PCDHA10 CNRS8 948 Q9UN75 PCDAC_HUMANProtocadherin alpha-12 (PCDH-alpha-12) PCDHA12 941 Q9Y5F3 PCDB1_HUMANProtocadherin beta-1 (PCDH-beta-1) PCDHB1 818 Q9Y5E4 PCDB5_HUMANProtocadherin beta-5 (PCDH-beta-5) PCDHB5 795 Q9UN66 PCDB8_HUMANProtocadherin beta-8 (PCDH-beta-8) (Protocadherin-3I) PCDHB8 PCDH3I 801Q9Y5F2 PCDBB_HUMAN Protocadherin beta-11 (PCDH-beta-11) PCDHB11 797Q9Y5F0 PCDBD_HUMAN Protocadherin beta-13 (PCDH-beta-13) PCDHB13 798UNQ332/PRO531 Q9Y5H1 PCDG2_HUMAN Protocadherin gamma-A2 (PCDH-gamma-A2)PCDHGA2 932 Q9Y5G4 PCDG9_HUMAN Protocadherin gamma-A9 (PCDH-gamma-A9)PCDHGA9 932 O60330 PCDGC_HUMAN Protocadherin gamma-A12 (PCDH-gamma-A12)(Cadherin-21) (Fibroblast cadherin-3) PCDHGA12 CDH21 932 FIB3 KIAA0588UNQ371/PRO707 Q9Y5G2 PCDGE_HUMAN Protocadherin gamma-B2 (PCDH-gamma-B2)PCDHGB2 931 Q9Y5F9 PCDGI_HUMAN Protocadherin gamma-B6 (PCDH-gamma-B6)PCDHGB6 930 Q9UN70 PCDGK_HUMAN Protocadherin gamma-C3 (PCDH-gamma-C3)(Protocadherin-2) (Protocadherin-43) (PC- PCDHGC3 PCDH2 934 43) O60245PCDH7_HUMAN Protocadherin-7 (Brain-heart protocadherin) (BH-Pcdh) PCDH7BHPCDH 1069 Q16549 PCSK7_HUMAN Proprotein convertase subtilisin/kexintype 7 (EC 3.4.21.—) (Lymphoma proprotein PCSK7 LPC PC7 785 convertase)(Prohormone convertase 7) (Proprotein convertase 7) (PC7) (ProproteinPC8 SPC7 convertase 8) (PC8) (hPC8) (Subtilisin/kexin-like protease PC7)Q9BQ51 PD1L2_HUMAN Programmed cell death 1 ligand 2 (PD-1 ligand 2)(PD-L2) (PDCD1 ligand 2) PDCD1LG2 B7DC 273 (Programmed death ligand 2)(Butyrophilin B7-DC) (B7-DC) (CD antigen CD273) CD273 PDCD1L2 PDL2P16284 PECA1_HUMAN Platelet endothelial cell adhesion molecule (PECAM-1)(EndoCAM) (GPIIA′) (PECA1) PECAM1 738 (CD antigen CD31) Q9NPG4PCD12_HUMAN Protocadherin-12 (Vascular cadherin-2) (Vascular endothelialcadherin-2) (VE-cad-2) PCDH12 1184 (VE-cadherin-2) UNQ395/PRO731 Q9Y5H9PCDA2_HUMAN Protocadherin alpha-2 (PCDH-alpha-2) PCDHA2 948 Q9UN72PCDA7_HUMAN Protocadherin alpha-7 (PCDH-alpha-7) PCDHA7 CNRS4 937 Q9Y5H6PCDA8_HUMAN Protocadherin alpha-8 (PCDH-alpha-8) PCDHA8 950 Q9Y5H5PCDA9_HUMAN Protocadherin alpha-9 (PCDH-alpha-9) PCDHA9 KIAA0345 950Q9Y5E2 PCDB7_HUMAN Protocadherin beta-7 (PCDH-beta-7) PCDHB7 793 Q9Y5E1PCDB9_HUMAN Protocadherin beta-9 (PCDH-beta-9) (Protocadherin-3H) PCDHB9PCDH3H 797 Q9Y5E9 PCDBE_HUMAN Protocadherin beta-14 (PCDH-beta-14)PCDHB14 798 Q9NRJ7 PCDBG_HUMAN Protocadherin beta-16 (PCDH-beta-16)(Protocadherin-3X) PCDHB16 776 KIAA1621 PCDH3X Q9H158 PCDC1_HUMANProtocadherin alpha-C1 (PCDH-alpha-C1) PCDHAC1 963 Q9Y5H4 PCDG1_HUMANProtocadherin gamma-A1 (PCDH-gamma-A1) PCDHGA1 931 Q9Y5G9 PCDG4_HUMANProtocadherin gamma-A4 (PCDH-gamma-A4) PCDHGA4 931 Q9Y5G3 PCDGD_HUMANProtocadherin gamma-B1 (PCDH-gamma-B1) PCDHGB1 927 Q9UN71 PCDGG_HUMANProtocadherin gamma-B4 (PCDH-gamma-B4) (Cadherin-20) (Fibroblastcadherin-2) PCDHGB4 CDH20 923 FIB2 Q9Y5G0 PCDGH_HUMAN Protocadheringamma-B5 (PCDH-gamma-B5) PCDHGB5 923 Q9Y5F8 PCDGJ_HUMAN Protocadheringamma-B7 (PCDH-gamma-B7) PCDHGB7 929 Q9Y5F7 PCDGL_HUMAN Protocadheringamma-C4 (PCDH-gamma-C4) PCDHGC4 938 P09619 PGFRB_HUMAN Platelet-derivedgrowth factor receptor beta (PDGF-R-beta) (PDGFR-beta) (EC 2.7.10.1)PDGFRB PDGFR 1106 (Beta platelet-derived growth factor receptor)(Beta-type platelet-derived growth factor PDGFR1 receptor) (CD140antigen-like family member B) (Platelet-derived growth factorreceptor 1) (PDGFR-1) (CD antigen CD140b) Q15116 PDCD1_HUMAN Programmedcell death protein 1 (Protein PD-1) (hPD-1) (CD antigen CD279) PDCD1 PD1288 P16234 PGFRA_HUMAN Platelet-derived growth factor receptor alpha(PDGF-R-alpha) (PDGFR-alpha) (EC PDGFRA PDGFR2 1089 2.7.10.1) (Alphaplatelet-derived growth factor receptor) (Alpha-type platelet-derivedRHEPDGFRA growth factor receptor) (CD140 antigen-like family member A)(CD140a antigen) (Platelet-derived growth factor alpha receptor)(Platelet-derived growth factor receptor 2) (PDGFR-2) (CD antigenCD140a) Q9NZ53 PDXL2_HUMAN Podocalyxin-like protein 2 (Endoglycan)PODXL2 605 UNQ1861/PRO3742 Q6UXB8 PI16_HUMAN Peptidase inhibitor 16(PI-16) (Cysteine-rich secretory protein 9) (CRISP-9) (PSP94- PI16CRISP9 463 binding protein) PSPBP PSEC0164 UNQ289/PRO328 Q9UKJ0PILRB_HUMAN Paired immunoglobulin-like type 2 receptor beta (Activatingreceptor PILR-beta) (Cell PILRB FDFACT 227 surface receptor FDFACT)PP1551 Q8IYJ0 PIANP_HUMAN PILR alpha-associated neural protein(PILR-associating neural protein) (Paired PIANP C12orf53 282immunoglobin-like type 2 receptor-associating neural protein) PANPUNQ828/PRO1755 P01833 PIGR_HUMAN Polymeric immunoglobulin receptor(PIgR) (Poly-Ig receptor) (Hepatocellular carcinoma- PIGR 764 associatedprotein TB6) [Cleaved into: Secretory component] Q9UKJ1 PILRA_HUMANPaired immunoglobulin-like type 2 receptor alpha (Cell surface receptorFDF03) PILRA 303 (Inhibitory receptor PILR-alpha) Q13018 PLA2R_HUMANSecretory phospholipase A2 receptor (PLA2-R) (PLA2R) (180 kDa secretoryPLA2R1 CLEC13C 1463 phospholipase A2 receptor) (C-type lectin domainfamily 13 member C) (M-type receptor) [Cleaved into: Soluble secretoryphospholipase A2 receptor (Soluble PLA2-R) (Soluble PLA2R)] Q8IUK5PLDX1_HUMAN Plexin domain-containing protein 1 (Tumor endothelial marker3) (Tumor endothelial PLXDC1 TEM3 500 marker 7) TEM7 O43157 PLXB1_HUMANPlexin-B1 (Semaphorin receptor SEP) PLXNB1 KIAA0407 2135 PLXN5 SEPO60486 PLXC1_HUMAN Plexin-C1 (Virus-encoded semaphorin protein receptor)(CD antigen CD232) PLXNC1 VESPR 1568 Q969N2 PIGT_HUMAN GPI transamidasecomponent PIG-T (Phosphatidylinositol-glycan biosynthesis class T PIGTCGI-06 578 protein) PSEC0163 UNQ716/PRO1379 P08F94 PKHD1_HUMANFibrocystin (Polycystic kidney and hepatic disease 1 protein)(Polyductin) (Tigmin) PKHD1 FCYT 4074 TIGM1 Q6P1J6 PLB1_HUMANPhospholipase B1, membrane-associated (Phospholipase B) (hPLB)(Phospholipase PLB1 PLB 1458 B/lipase) (PLB/LIP) [Includes:Phospholipase A2 (EC 3.1.1.4); Lysophospholipase (EC 3.1.1.5)] Q8TEM1PO210_HUMAN Nuclear pore membrane glycoprotein 210 (Nuclear pore proteingp210) (Nuclear NUP210 KIAA0906 1887 envelope pore membrane protein POM210) (POM210) (Nucleoporin Nup210) (Pore PSEC0245 membrane protein of210 kDa) O00168 PLM_HUMAN Phospholemman (FXYD domain-containing iontransport regulator 1) FXYD1 PLM 92 P51805 PLXA3_HUMAN Plexin-A3(Plexin-4) (Semaphorin receptor SEX) PLXNA3 PLXN4 1871 SEX Q9UIW2PLXA1_HUMAN Plexin-A1 (Semaphorin receptor NOV) PLXNA1 NOV 1896 PLXN1O75051 PLXA2_HUMAN Plexin-A2 (Semaphorin receptor OCT) PLXNA2 KIAA04631894 OCT PLXN2 UNQ209/PRO235 Q8TBF5 PIGX_HUMANPhosphatidylinositol-glycan biosynthesis class X protein (PIG-X) PIGX258 P40967 PMEL_HUMAN Melanocyte protein PMEL (ME20-M) (ME20M)(Melanocyte protein Pmel 17) PMEL D12S53E 661 (Melanocyteslineage-specific antigen GP100) (Melanoma-associated ME20 antigen)PMEL17 SILV (P1) (P100) (Premelanosome protein) (Silver locus proteinhomolog) [Cleaved into: M- alpha (95 kDa melanocyte-specific secretedglycoprotein) (P26) (Secreted melanoma- associated ME20 antigen)(ME20-S) (ME20S); M-beta] Q8IY17 PLPL6_HUMAN Neuropathy target esterase(EC 3.1.1.5) (Patatin-like phospholipase domain-containing PNPLA6 NTE1366 protein 6) Q9BZG2 PPAT_HUMAN Testicular acid phosphatase (EC3.1.3.2) ACPT 426 Q86XR5 PRIMA_HUMAN Proline-rich membrane anchor 1(PRiMA) PRIMA1 153 Q9HCM2 PLXA4_HUMAN Plexin-A4 PLXNA4 KIAA1550 1894PLXNA4A PLXNA4B UNQ2820/PRO34003 O15031 PLXB2_HUMAN Plexin-B2 (MM1)PLXNB2 KIAA0315 1838 Q9ULL4 PLXB3_HUMAN Plexin-B3 PLXNB3 KIAA1206 1909PLXN6 O00592 PODXL_HUMAN Podocalyxin (GCTM-2 antigen) (Gp200)(Podocalyxin-like protein 1) (PC) (PCLP-1) PODXL PCLP 558 PCLP1 Q8N131PORIM_HUMAN Porimin (Keratinocytes-associated transmembrane protein 3)(KCT-3) (Pro-oncosis TMEM123 KCT3 208 receptor inducing membrane injury)(Transmembrane protein 123) PSEC0111 UNQ641/PRO1271 P15309 PPAP_HUMANProstatic acid phosphatase (PAP) (EC 3.1.3.2) (5′-nucleotidase) (5′-NT)(EC 3.1.3.5) ACPP 386 (Ecto-5′-nucleotidase) (Thiamine monophosphatase)(TMPase) [Cleaved into: PAPf39] Q5SGD2 PPM1L_HUMAN Protein phosphatase1L (EC 3.1.3.16) (Protein phosphatase 1-like) (Protein phosphatase PPM1LPP2CE 360 2C isoform epsilon) (PP2C-epsilon) P16471 PRLR_HUMAN Prolactinreceptor (PRL-R) PRLR 622 Q6UWB4 PRS55_HUMAN Serine protease 55 (EC3.4.21.—) (Testis serine protease 1) (T-SP1) PRSS55 TSP1 352UNQ9391/PRO34284 P10586 PTPRF_HUMAN Receptor-type tyrosine-proteinphosphatase F (EC 3.1.3.48) (Leukocyte common antigen PTPRF LAR 1907related) (LAR) P28827 PTPRM_HUMAN Receptor-type tyrosine-proteinphosphatase mu (Protein-tyrosine phosphatase mu) (R- PTPRM PTPRL1 1452PTP-mu) (EC 3.1.3.48) Q16849 PTPRN_HUMAN Receptor-type tyrosine-proteinphosphatase-like N (R-PTP-N) (Islet cell antigen 512) (ICA PTPRN ICA3979 512) (Islet cell autoantigen 3) (PTP IA-2) ICA512 Q13332 PTPRS_HUMANReceptor-type tyrosine-protein phosphatase S (R-PTP-S) (EC 3.1.3.48)(Receptor-type PTPRS 1948 tyrosine-protein phosphatase sigma)(R-PTP-sigma) Q6ISU1 PTCRA_HUMAN Pre T-cell antigen receptor alpha(pT-alpha) (pTa) (pT-alpha-TCR) PTCRA 281 P53801 PTTG_HUMAN Pituitarytumor-transforming gene 1 protein-interacting protein (Pituitary tumor-PTTG1IP C21orf1 180 transforming gene protein-binding factor) (PBF)(PTTG-binding factor) C21orf3 Q13308 PTK7_HUMAN Inactivetyrosine-protein kinase 7 (Colon carcinoma kinase 4) (CCK-4)(Protein-tyrosine PTK7 CCK4 1070 kinase 7) (Pseudo tyrosine kinasereceptor 7) (Tyrosine-protein kinase-like 7) P23468 PTPRD_HUMANReceptor-type tyrosine-protein phosphatase delta (Protein-tyrosinephosphatase delta) PTPRD 1912 (R-PTP-delta) (EC 3.1.3.48) Q15262PTPRK_HUMAN Receptor-type tyrosine-protein phosphatase kappa(Protein-tyrosine phosphatase kappa) PTPRK PTPK 1439 (R-PTP-kappa) (EC3.1.3.48) Q9UMZ3 PTPRQ_HUMAN Phosphatidylinositol phosphatase PTPRQ (EC3.1.3.—) (Receptor-type tyrosine-protein PTPRQ 2332 phosphatase Q)(PTP-RQ) (R-PTP-Q) (EC 3.1.3.48) P23467 PTPRB_HUMAN Receptor-typetyrosine-protein phosphatase beta (Protein-tyrosine phosphatase beta)(R- PTPRB PTPB 1997 PTP-beta) (EC 3.1.3.48) (Vascular endothelialprotein tyrosine phosphatase) (VE-PTP) Q9HD43 PTPRH_HUMAN Receptor-typetyrosine-protein phosphatase H (R-PTP-H) (EC 3.1.3.48) (Stomach PTPRHSAP1 1115 cancer-associated protein tyrosine phosphatase 1) (SAP-1)(Transmembrane-type protein-tyrosine phosphatase type H) Q16827PTPRO_HUMAN Receptor-type tyrosine-protein phosphatase O (R-PTP-O) (EC3.1.3.48) (Glomerular PTPRO GLEPP1 1216 epithelial protein 1) (Proteintyrosine phosphatase U2) (PTP-U2) (PTPase U2) PTPU2 Q15256 PTPRR_HUMANReceptor-type tyrosine-protein phosphatase R (R-PTP-R) (EC 3.1.3.48)(Ch-1PTPase) PTPRR ECPTP 657 (NC-PTPCOM1) (Protein-tyrosine phosphatasePCPTP1) PTPRQ P15151 PVR_HUMAN Poliovirus receptor (Nectin-like protein5) (NECL-5) (CD antigen CD155) PVR PVS 417 P18433 PTPRA_HUMANReceptor-type tyrosine-protein phosphatase alpha (Protein-tyrosinephosphatase alpha) PTPRA PTPA 802 (R-PTP-alpha) (EC 3.1.3.48) PTPRL2P08575 PTPRC_HUMAN Receptor-type tyrosine-protein phosphatase C (EC3.1.3.48) (Leukocyte common PTPRC CD45 1304 antigen) (L-CA) (T200) (CDantigen CD45) O14522 PTPRT_HUMAN Receptor-type tyrosine-proteinphosphatase T (R-PTP-T) (EC 3.1.3.48) (Receptor-type PTPRT KIAA0283 1441tyrosine-protein phosphatase rho) (RPTP-rho) Q92729 PTPRU_HUMANReceptor-type tyrosine-protein phosphatase U (R-PTP-U) (EC 3.1.3.48)(Pancreatic PTPRU FMI PCP2 1446 carcinoma phosphatase 2) (PCP-2)(Protein-tyrosine phosphatase J) (PTP-J) (hPTP-J) PTPRO(Protein-tyrosine phosphatase pi) (PTP pi) (Protein-tyrosine phosphatasereceptor omicron) (PTP-RO) (Receptor-type protein-tyrosine phosphatasepsi) (R-PTP-psi) P23471 PTPRZ_HUMAN Receptor-type tyrosine-proteinphosphatase zeta (R-PTP-zeta) (EC 3.1.3.48) (Protein- PTPRZ1 HTPZP2 2315tyrosine phosphatase receptor type Z polypeptide 1) (Protein-tyrosinephosphatase PTPRZ PTPRZ2 receptor type Z polypeptide 2) (R-PTP-zeta-2)PTPZ Q9NXS2 QPCTL_HUMAN Glutaminyl-peptide cyclotransferase-like protein(EC 2.3.2.5) (Golgi-resident glutaminyl- QPCTL 382 peptidecyclotransferase) (isoQC) (gQC) Q92932 PTPR2_HUMAN Receptor-typetyrosine-protein phosphatase N2 (R-PTP-N2) (EC 3.1.3.48) (Islet cellPTPRN2 KIAA0387 1015 autoantigen-related protein) (IAR) (ICAAR)(Phogrin) P23469 PTPRE_HUMAN Receptor-type tyrosine-protein phosphataseepsilon (Protein-tyrosine phosphatase PTPRE 700 epsilon) (R-PTP-epsilon)(EC 3.1.3.48) P23470 PTPRG_HUMAN Receptor-type tyrosine-proteinphosphatase gamma (Protein-tyrosine phosphatase PTPRG PTPG 1445 gamma)(R-PTP-gamma) (EC 3.1.3.48) Q12913 PTPRJ_HUMAN Receptor-typetyrosine-protein phosphatase eta (Protein-tyrosine phosphatase eta) (R-PTPRJ DEP1 1337 PTP-eta) (EC 3.1.3.48) (Density-enhanced phosphatase 1)(DEP-1) (HPTP eta) (Protein- tyrosine phosphatase receptor type J)(R-PTP-J) (CD antigen CD148) Q15109 RAGE_HUMAN Advanced glycosylationend product-specific receptor (Receptor for advanced AGER RAGE 404glycosylation end products) Q6UX71 PXDC2_HUMAN Plexin domain-containingprotein 2 (Tumor endothelial marker 7-related protein) PLXDC2 TEM7R 529UNQ2514/PRO6003 O60894 RAMP1_HUMAN Receptor activity-modifying protein 1(Calcitonin-receptor-like receptor activity-modifying RAMP1 148protein 1) (CRLR activity-modifying protein 1) O60895 RAMP2_HUMANReceptor activity-modifying protein 2 (Calcitonin-receptor-like receptoractivity-modifying RAMP2 175 protein 2) (CRLR activity-modifying protein2) O60896 RAMP3_HUMAN Receptor activity-modifying protein 3(Calcitonin-receptor-like receptor activity-modifying RAMP3 148 protein3) (CRLR activity-modifying protein 3) Q8IUW5 RELL1_HUMAN RELT-likeprotein 1 RELL1 PSEC0162 271 O75787 RENR_HUMAN Renin receptor (ATPaseH(+)-transporting lysosomal accessory protein 2) (ATPase H(+)- ATP6AP2ATP6IP2 350 transporting lysosomal-interacting protein 2) (ER-localizedtype I transmembrane adaptor) CAPER ELDF10 (Embryonic liverdifferentiation factor 10) (N14F) (Renin/prorenin receptor) (VacuolarATP HT028 MSTP009 synthase membrane sector-associated protein M8-9)(ATP6M8-9) (V-ATPase M8.9 PSEC0072 subunit) Q6H3X3 RET1G_HUMAN Retinoicacid early transcript 1G protein (UL-16 binding protein 5) (ULBP5)RAET1G 334 P07949 RET_HUMAN Proto-oncogene tyrosine-protein kinasereceptor Ret (EC 2.7.10.1) (Cadherin family RET CDHF12 1114 member 12)(Proto-oncogene c-Ret) [Cleaved into: Soluble RET kinase fragment;CDHR16 PTC Extracellular cell-membrane anchored RET cadherin 120 kDafragment] RET51 Q9ULK6 RN150_HUMAN RING finger protein 150 RNF150KIAA1214 438 Q9Y6N7 ROBO1_HUMAN Roundabout homolog 1 (Deleted in Utwenty twenty) (H-Robo-1) ROBO1 DUTT1 1651 Q01974 ROR2_HUMANTyrosine-protein kinase transmembrane receptor ROR2 (EC 2.7.10.1)(Neurotrophic ROR2 NTRKR2 943 tyrosine kinase, receptor-related 2)P04843 RPN1_HUMAN Dolichyl-diphosphooligosaccharide--proteinglycosyltransferase subunit 1 (EC 2.4.99.18) RPN1 607(Dolichyl-diphosphooligosaccharide--protein glycosyltransferase 67 kDasubunit) (Ribophorin I) (RPN-I) (Ribophorin-1) Q68DV7 RNF43_HUMAN E3ubiquitin-protein ligase RNF43 (EC 6.3.2.—) (RING finger protein 43)RNF43 783 Q04912 RON_HUMAN Macrophage-stimulating protein receptor (MSPreceptor) (EC 2.7.10.1) (CDw136) MST1R PTK8 RON 1400 (Protein-tyrosinekinase 8) (p185-Ron) (CD antigen CD136) [Cleaved into: Macrophage-stimulating protein receptor alpha chain; Macrophage-stimulating proteinreceptor beta chain] Q96MS0 ROBO3_HUMAN Roundabout homolog 3(Roundabout-like protein 3) ROBO3 1386 Q01973 ROR1_HUMAN Inactivetyrosine-protein kinase transmembrane receptor ROR1 (Neurotrophictyrosine ROR1 NTRKR1 937 kinase, receptor-related 1) P08922 ROS1_HUMANProto-oncogene tyrosine-protein kinase ROS (EC 2.7.10.1) (Proto-oncogenec-Ros) ROS1 MCF3 ROS 2347 (Proto-oncogene c-Ros-1) (Receptor tyrosinekinase c-ros oncogene 1) (c-Ros receptor tyrosine kinase) Q9HCK4ROBO2_HUMAN Roundabout homolog 2 ROBO2 KIAA1568 1378 P34925 RYK_HUMANTyrosine-protein kinase RYK (EC 2.7.10.1) RYK JTK5A 604 Q9HBV2SACA1_HUMAN Sperm acrosome membrane-associated protein 1 (Spermacrosomal membrane- SPACA1 SAMP32 294 associated protein 32) P31431SDC4_HUMAN Syndecan-4 (SYND4) (Amphiglycan) (Ryudocan core protein) SDC4198 P21583 SCF_HUMAN Kit ligand (Mast cell growth factor) (MGF) (Stemcell factor) (SCF) (c-Kit ligand) [Cleaved KITLG MGF SCF 273 into:Soluble KIT ligand (sKITLG)] O60939 SCN2B_HUMAN Sodium channel subunitbeta-2 SCN2B 215 UNQ326/PRO386 Q8IWT1 SCN4B_HUMAN Sodium channel subunitbeta-4 SCN4B 228 P18827 SDC1_HUMAN Syndecan-1 (SYND1) (CD antigen CD138)SDC1 SDC 310 O75056 SDC3_HUMAN Syndecan-3 (SYND3) SDC3 KIAA0468 442Q9NTN9 SEM4G_HUMAN Semaphorin-4G SEMA4G KIAA1619 838 W5XKT8 SACA6_HUMANSperm acrosome membrane-associated protein 6 (BACHELOR-like protein)SPACA6 SPACA6P 324 UNQ2487/PRO5774 Q96BY9 SARAF_HUMAN Store-operatedcalcium entry-associated regulatory factor (SARAF) (SOCE-associatedSARAF TMEM66 339 regulatory factor) (HBV X-transactivated gene 3protein) (HBV XAg-transactivated protein XTP3 HSPC035 3) (ProteinFOAP-7) (Transmembrane protein 66) NPD003 PSEC0019 UNQ1967/PRO4499Q13591 SEM5A_HUMAN Semaphorin-5A (Semaphorin-F) (Sema F) SEMA5A SEMAF1074 Q53EL9 SEZ6_HUMAN Seizure protein 6 homolog (SEZ-6) (hSEZ-6) SEZ6994 Q9NY72 SCN3B_HUMAN Sodium channel subunit beta-3 SCN3B KIAA1158 215Q8WVN6 SCTM1_HUMAN Secreted and transmembrane protein 1 (Protein K-12)SECTM1 K12 248 Q9UBV2 SE1L1_HUMAN Protein sel-1 homolog 1 (Suppressor oflin-12-like protein 1) (Sel-1L) SEL1L TSA305 794 UNQ128/PRO1063 Q9NPR2SEM4B_HUMAN Semaphorin-4B SEMA4B KIAA1745 832 SEMAC UNQ749/PRO1480O95754 SEM4F_HUMAN Semaphorin-4F (Semaphorin-M) (Sema M) (Semaphorin-W)(Sema W) SEMA4F SEMAM 770 SEMAW Q96RL6 SIG11_HUMAN Sialic acid-bindingIg-like lectin 11 (Sialic acid-binding lectin 11) (Siglec-11) SIGLEC11698 UNQ9222/PRO28718 Q07699 SCN1B_HUMAN Sodium channel subunit beta-1SCN1B 218 P34741 SDC2_HUMAN Syndecan-2 (SYND2) (Fibroglycan) (Heparansulfate proteoglycan core protein) (HSPG) SDC2 HSPG1 201 (CD antigenCD362) Q7Z5N4 SDK1_HUMAN Protein sidekick-1 SDK1 2213 Q58EX2 SDK2_HUMANProtein sidekick-2 SDK2 KIAA1514 2172 Q5TEA6 SE1L2_HUMAN Protein sel-1homolog 2 (Suppressor of lin-12-like protein 2) (Sel-1L2) SEL1L2C20orf50 688 Q9BYH1 SE6L1_HUMAN Seizure 6-like protein SEZ6L KIAA09271024 UNQ2542/PRO6094 Q14242 SELPL_HUMAN P-selectin glycoprotein ligand 1(PSGL-1) (Selectin P ligand) (CD antigen CD162) SELPLG 412 Q9H3T2SEM6C_HUMAN Semaphorin-6C (Semaphorin-Y) (Sema Y) SEMA6C KIAA1869 930SEMAY Q96DD7 SHSA4_HUMAN Protein shisa-4 (Transmembrane protein 58)SHISA4 C1orf40 197 TMEM58 UNQ583/PRO1153 Q9P0V8 SLAF8_HUMAN SLAM familymember 8 (B-lymphocyte activator macrophage expressed) (BCM-like SLAMF8BLAME 285 membrane protein) (CD antigen CD353) Q9H3T3 SEM6B_HUMANSemaphorin-6B (Semaphorin-Z) (Sema Z) SEMA6B SEMAN 888 SEMAZUNQ1907/PRO4353 Q8NFY4 SEM6D_HUMAN Semaphorin-6D SEMA6D KIAA1479 1073O94933 SLIK3_HUMAN SLIT and NTRK-like protein 3 SLITRK3 KIAA0848 977Q6UXD5 SE6L2_HUMAN Seizure 6-like protein 2 SEZ6L2 PSK 910UNQ1903/PRO4349 Q9C0C4 SEM4C_HUMAN Semaphorin-4C SEMA4C KIAA1739 833SEMAI UNQ5855/PRO34487 Q92854 SEM4D_HUMAN Semaphorin-4D (A8) (BB18)(GR3) (CD antigen CD100) SEMA4D C9orf164 862 CD100 SEMAJ P78324SHPS1_HUMAN Tyrosine-protein phosphatase non-receptor type substrate 1(SHP substrate 1) (SHPS-1) SIRPA BIT MFR 504 (Brain Ig-like moleculewith tyrosine-based activation motifs) (Bit) (CD172 antigen-like MYD1PTPNS1 family member A) (Inhibitory receptor SHPS-1) (Macrophage fusionreceptor) (MyD-1 SHPS1 SIRP antigen) (Signal-regulatory protein alpha-1)(Sirp-alpha-1) (Signal-regulatory protein alpha-2) (Sirp-alpha-2)(Signal-regulatory protein alpha-3) (Sirp-alpha-3) (p84) (CD antigenCD172a) Q8N114 SHSA5_HUMAN Protein shisa-5 (PutativeNF-kappa-B-activating protein 120) (Scotin) SHISA5 SCOTIN 240 PSEC0133B8ZZ34 SHSA8_HUMAN Putative protein shisa-8 SHISA8 C22orf17 492 Q96PQ1SIG12_HUMAN Sialic acid-binding Ig-like lectin 12 (Siglec-12) (Sialicacid-binding Ig-like lectin-like 1) SIGLEC12 595 (Siglec-L1) SIGLECL1SLG UNQ9215/PRO34042 Q5JXA9 SIRB2_HUMAN Signal-regulatory protein beta-2(SIRP-beta-2) (Protein tyrosine phosphatase non- SIRPB2 PTPN1L 342receptor type substrate 1-like 3) (Protein tyrosine phosphatasenon-receptor type PTPNS1L3 substrate protein) Q9P1W8 SIRPG_HUMANSignal-regulatory protein gamma (SIRP-gamma) (CD172 antigen-like familymember B) SIRPG SIRPB2 387 (Signal-regulatory protein beta-2) (SIRP-b2)(SIRP-beta-2) (CD antigen CD172g) Q9BQ49 SMIM7_HUMAN Small integralmembrane protein 7 SMIM7 C19orf42 75 Q9H3S1 SEM4A_HUMAN Semaphorin-4A(Semaphorin-B) (Sema B) SEMA4A SEMAB 761 SEMB UNQ783/PRO1317 Q9H2E6SEM6A_HUMAN Semaphorin-6A (Semaphorin VIA) (Sema VIA) (Semaphorin-6A-1)(SEMA6A-1) SEMA6A KIAA1368 1030 SEMAQ B4DS77 SHSA9_HUMAN Protein shisa-9SHISA9 424 A6NMB1 SIG16_HUMAN Sialic acid-binding Ig-like lectin 16(Siglec-16) (Siglec-P16) SIGLEC16 481 SIGLECP16 Q9NYZ4 SIGL8_HUMANSialic acid-binding Ig-like lectin 8 (Siglec-8) (Sialoadhesin familymember 2) (SAF-2) SIGLEC8 SAF2 499 Q9UIB8 SLAF5_HUMAN SLAM family member5 (Cell surface antigen MAX.3) (Hly9-beta) (Leukocyte CD84 SLAMF5 345differentiation antigen CD84) (Signaling lymphocytic activation molecule5) (CD antigen CD84) Q16586 SGCA_HUMAN Alpha-sarcoglycan (Alpha-SG) (50kDa dystrophin-associated glycoprotein) (50DAG) SGCA ADL DAG2 387(Adhalin) (Dystroglycan-2) A0PJX4 SHSA3_HUMAN Protein shisa-3 homologSHISA3 238 Q96LC7 SIG10_HUMAN Sialic acid-binding Ig-like lectin 10(Siglec-10) (Siglec-like protein 2) SIGLEC10 SLG2 697 UNQ477/PRO940O15389 SIGL5_HUMAN Sialic acid-binding Ig-like lectin 5 (Siglec-5) (CD33antigen-like 2) (Obesity-binding protein SIGLEC5 CD33L2 551 2) (OB-BP2)(OB-binding protein 2) (CD antigen CD170) OBBP2 O43699 SIGL6_HUMANSialic acid-binding Ig-like lectin 6 (Siglec-6) (CD33 antigen-like 1)(CDw327) (Obesity- SIGLEC6 CD33L 453 binding protein 1) (OB-BP1) (CDantigen CD327) CD33L1 OBBP1 Q9Y336 SIGL9_HUMAN Sialic acid-bindingIg-like lectin 9 (Siglec-9) (CDw329) (Protein FOAP-9) (CD antigenSIGLEC9 463 CD329) UNQ668/PRO1302 O00241 SIRB1_HUMAN Signal-regulatoryprotein beta-1 (SIRP-beta-1) (CD172 antigen-like family member B) SIRPB1398 (CD antigen CD172b) Q13291 SLAF1_HUMAN Signaling lymphocyticactivation molecule (CDw150) (IPO-3) (SLAM family member 1) SLAMF1 SLAM335 (CD antigen CD150) Q96DU3 SLAF6_HUMAN SLAM family member 6(Activating NK receptor) (NK-T-B-antigen) (NTB-A) (CD antigen SLAMF6KALI 332 CD352) UNQ6123/PRO20080 O94991 SLIK5_HUMAN SLIT and NTRK-likeprotein 5 (Leucine-rich repeat-containing protein 11) SLITRK5 KIAA0918958 LRRC11 Q96PQ0 SORC2_HUMAN VPS10 domain-containing receptor SorCS2SORCS2 KIAA1329 1159 Q6UWI4 SHSA2_HUMAN Protein shisa-2 homolog(Transmembrane protein 46) SHISA2 C13orf13 295 TMEM46 UNQ9166/PRO28631Q6ZMC9 SIG15_HUMAN Sialic acid-binding Ig-like lectin 15 (Siglec-15)(CD33 antigen-like 3) SIGLEC15 CD33L3 328 Q9Y286 SIGL7_HUMAN Sialicacid-binding Ig-like lectin 7 (Siglec-7) (Adhesion inhibitory receptormolecule 1) SIGLEC7 AIRM1 467 (AIRM-1) (CDw328) (D-siglec) (QA79membrane protein) (p75) (CD antigen CD328) Q96A28 SLAF9_HUMAN SLAMfamily member 9 (CD2 family member 10) (CD2F-10) (CD84 homolog 1) (CD84-SLAMF9 CD2F10 289 H1) UNQ1938/PRO4421 Q9H156 SLIK2_HUMAN SLIT andNTRK-like protein 2 SLITRK2 CXorf2 845 KIAA1854 SLITL1 UNQ9197/PRO34756Q8IW52 SLIK4_HUMAN SLIT and NTRK-like protein 4 SLITRK4 837 A6NGZ8SMIM9_HUMAN Small integral membrane protein 9 SMIM9 CXorf68 99 Q8WY21SORC1_HUMAN VPS10 domain-containing receptor SorCS1 (hSorCS) SORCS1SORCS 1168 Q92673 SORL_HUMAN Sortilin-related receptor (Low-densitylipoprotein receptor relative with 11 ligand-binding SORL1 C11orf32 2214repeats) (LDLR relative with 11 ligand-binding repeats) (LR11) (SorLA-1)(Sorting protein- related receptor containing LDLR class A repeats)(SorLA) Q99523 SORT_HUMAN Sortilin (100 kDa NT receptor) (Glycoprotein95) (Gp95) (Neurotensin receptor 3) (NT3) SORT1 831 (NTR3) Q9Y3P8SIT1_HUMAN Signaling threshold-regulating transmembrane adapter 1(SHP2-interacting SIT1 SIT 196 transmembrane adapter protein)(Suppression-inducing transmembrane adapter 1) (gp30/40) Q9NQ25SLAF7_HUMAN SLAM family member 7 (CD2 subset 1) (CD2-likereceptor-activating cytotoxic cells) SLAMF7 CS1 335 (CRACC) (Membraneprotein FOAP-12) (Novel Ly9) (Protein 19A) (CD antigen CD319)UNQ576/PRO1138 Q96PX8 SLIK1_HUMAN SLIT and NTRK-like protein 1(Leucine-rich repeat-containing protein 12) SLITRK1 KIAA1910 696 LRRC12UNQ233/PRO266 Q9H5Y7 SLIK6_HUMAN SLIT and NTRK-like protein 6 SLITRK6841 Q6ZSJ9 SHSA6_HUMAN Protein shisa-6 homolog SHISA6 500 Q08ET2SIG14_HUMAN Sialic acid-binding Ig-like lectin 14 (Siglec-14) SIGLEC14396 UNQ294/PRO333 Q5TFQ8 SIRBL_HUMAN Signal-regulatory protein beta-1isoform 3 (SIRP-beta-1 isoform 3) SIRPB1 398 Q9UPU3 SORC3_HUMAN VPS10domain-containing receptor SorCS3 SORCS3 KIAA1059 1222 O43291SPIT2_HUMAN Kunitz-type protease inhibitor 2 (Hepatocyte growth factoractivator inhibitor type 2) (HAI- SPINT2 HAI2 KOP 252 2) (Placentalbikunin) Q9BZZ2 SN_HUMAN Sialoadhesin (Sialic acid-binding Ig-likelectin 1) (Siglec-1) (CD antigen CD169) SIGLEC1 SN 1709 Q9P246STIM2_HUMAN Stromal interaction molecule 2 STIM2 KIAA1482 746 Q9UBS9SUCO_HUMAN SUN domain-containing ossification factor (Membrane proteinCH1) (Protein SUCO C1orf9 CH1 1254 osteopotentia homolog) (SUN-likeprotein 1) OPT SLP1 Q96GP6 SREC2_HUMAN Scavenger receptor class F member2 (SRECRP-1) (Scavenger receptor expressed by SCARF2 SREC2 870endothelial cells 2 protein) (SREC-II) SREPCR P43307 SSRA_HUMANTranslocon-associated protein subunit alpha (TRAP-alpha) (Signalsequence receptor SSR1 TRAPA 286 subunit alpha) (SSR-alpha) PSEC0262Q5VX71 SUSD4_HUMAN Sushi domain-containing protein 4 SUSD4 490UNQ196/PRO222 P43308 SSRB_HUMAN Translocon-associated protein subunitbeta (TRAP-beta) (Signal sequence receptor SSR2 TRAPB 183 subunit beta)(SSR-beta) HSD25 P51571 SSRD_HUMAN Translocon-associated protein subunitdelta (TRAP-delta) (Signal sequence receptor SSR4 TRAPD 173 subunitdelta) (SSR-delta) Q13586 STIM1_HUMAN Stromal interaction molecule 1STIM1 GOK 685 Q14162 SREC_HUMAN Scavenger receptor class F member 1(Acetyl LDL receptor) (Scavenger receptor SCARF1 KIAA0149 830 expressedby endothelial cells 1) (SREC-I) SREC Q92537 SUSD6_HUMAN Sushidomain-containing protein 6 (Drug-activated gene overexpressed protein)SUSD6 DRAGO 303 KIAA0247 Q9NY15 STAB1_HUMAN Stabilin-1 (Fasciclin,EGF-like, laminin-type EGF-like and link domain-containing STAB1 FEEL12570 scavenger receptor 1) (FEEL-1) (MS-1 antigen) KIAA0246 Q8WWQ8STAB2_HUMAN Stabilin-2 (FAS1 EGF-like and X-link domain-containingadhesion molecule 2) (Fasciclin, STAB2 FEEL2 2551 EGF-like, laminin-typeEGF-like and link domain-containing scavenger receptor 2) (FEEL- FELLFEX2 HARE 2) (Hyaluronan receptor for endocytosis) [Cleaved into: 190kDa form stabilin-2 (190 kDa hyaluronan receptor for endocytosis)]O60279 SUSD5_HUMAN Sushi domain-containing protein 5 SUSD5 KIAA0527 629Q9UGT4 SUSD2_HUMAN Sushi domain-containing protein 2 SUSD2 822 Q9UQF0SYCY1_HUMAN Syncytin-1 (Endogenous retrovirus group W member 1) (Env-W)(Envelope polyprotein ERVW-1 ERVWE1 538 gPr73) (Enverin) (HERV-7qEnvelope protein) (HERV-W envelope protein) (HERV- W_7q21.2 provirusancestral Env polyprotein) (Syncytin) [Cleaved into: Surface protein(SU) (gp50); Transmembrane protein (TM) (gp24)] Q6UWL2 SUSD1_HUMAN Sushidomain-containing protein 1 SUSD1 747 UNQ2438/PRO4999 Q8N3T6 T132C_HUMANTransmembrane protein 132C TMEM132C 1108 A2VDJ0 T131L_HUMANTransmembrane protein 131-like KIAA0922 1609 TMEM131L Q6IEE7 T132E_HUMANTransmembrane protein 132E TMEM132E 984 Q14DG7 T132B_HUMAN Transmembraneprotein 132B TMEM132B 1078 KIAA1786 KIAA1906 P09758 TACD2_HUMANTumor-associated calcium signal transducer 2 (Cell surface glycoproteinTrop-2) TACSTD2 GA733-1 323 (Membrane component chromosome 1 surfacemarker 1) (Pancreatic carcinoma marker M1S1 TROP2 protein GA733-1)Q14C87 T132D_HUMAN Transmembrane protein 132D (Mature oligodendrocytestransmembrane protein) (Mature TMEM132D 1099 OL transmembrane protein)HBE120 KIAA1944 MOLT Q96GX1 TECT2_HUMAN Tectonic-2 TCTN2 C12orf38 697TECT2 Q24JP5 T132A_HUMAN Transmembrane protein 132A (HSPA5-bindingprotein 1) TMEM132A 1023 HSPA5BP1 KIAA1583 B6A8C7 TARM1_HUMANT-cell-interacting, activating receptor on myeloid cells protein 1(OSCAR-like transcript-2 TARM1 271 protein) (OLT-2) P40200 TACT_HUMANT-cell surface protein tactile (Cell surface antigen CD96) (Tcell-activated increased late CD96 585 expression protein) (CD antigenCD96) Q9UIK5 TEFF2_HUMAN Tomoregulin-2 (TR-2) (Hyperplastic polyposisprotein 1) (Transmembrane protein with TMEFF2 HPP1 374 EGF-like and twofollistatin-like domains) TENB2 TPEF UNQ178/PRO204 P36897 TGFR1_HUMANTGF-beta receptor type-1 (TGFR-1) (EC 2.7.11.30) (Activin A receptortype II-like protein TGFBR1 ALK5 503 kinase of 53 kD) (Activinreceptor-like kinase 5) (ALK-5) (ALK5) (Serine/threonine-protein SKR4kinase receptor R4) (SKR4) (TGF-beta type I receptor) (Transforminggrowth factor-beta receptor type I) (TGF-beta receptor type I)(TbetaR-I) Q9NS62 THSD1_HUMAN Thrombospondin type-1 domain-containingprotein 1 (Transmembrane molecule with THSD1 TMTSP 852 thrombospondinmodule) UNQ3010/PRO9769 Q02763 TIE2_HUMAN Angiopoietin-1 receptor (EC2.7.10.1) (Endothelial tyrosine kinase) (Tunica interna TEK TIE2 VMCM1124 endothelial cell kinase) (Tyrosine kinase with Ig and EGF homologydomains-2) VMCM1 (Tyrosine-protein kinase receptor TEK)(Tyrosine-protein kinase receptor TIE-2) (hTIE2) (p140 TEK) (CD antigenCD202b) P13726 TF_HUMAN Tissue factor (TF) (Coagulation factor III)(Thromboplastin) (CD antigen CD142) F3 295 Q495A1 TIGIT_HUMAN T-cellimmunoreceptor with Ig and ITIM domains (V-set and immunoglobulindomain- TIGIT VSIG9 244 containing protein 9) (V-set and transmembranedomain-containing protein 3) VSTM3 Q03167 TGBR3_HUMAN Transforminggrowth factor beta receptor type 3 (TGF-beta receptor type 3) (TGFR-3)TGFBR3 851 (Betaglycan) (Transforming growth factor beta receptor III)(TGF-beta receptor type III) O43493 TGON2_HUMAN Trans-Golgi networkintegral membrane protein 2 (TGN38 homolog) (TGN46) (TGN48) TGOLN2 TGN46480 (Trans-Golgi network protein TGN51) TGN51 Q9BXR5 TLR10_HUMANToll-like receptor 10 (CD antigen CD290) TLR10 811 UNQ315/PRO358 Q8IYR6TEFF1_HUMAN Tomoregulin-1 (TR-1) (H7365) (Transmembrane protein withEGF-like and one follistatin- TMEFF1 C9orf2 380 like domain) Q8N3G9TM130_HUMAN Transmembrane protein 130 TMEM130 435 UNQ719/PRO1383 Q4KMG9TM52B_HUMAN Transmembrane protein 52B TMEM52B C12orf59 183UNQ5927/PRO19821 Q9BZD6 TMG4_HUMAN Transmembrane gamma-carboxyglutamicacid protein 4 (Praline-rich gamma- PRRG4 PRGP4 226 carboxyglutamic acidprotein 4) (Proline-rich Gla protein 4) TMG4 Q8NEW7 TMIE_HUMANTransmembrane inner ear expressed protein TMIE 156 Q9HBJ8 TMM27_HUMANCollectrin (Transmembrane protein 27) TMEM27 222 UNQ679/PRO1312 Q6UXU6TMM92_HUMAN Transmembrane protein 92 TMEM92 159 UNQ5801/PRO19608 Q6NUS6TECT3_HUMAN Tectonic-3 TCTN3 C10orf61 607 TECT3 PSEC0041 UNQ1881/PRO4324P35590 TIE1_HUMAN Tyrosine-protein kinase receptor Tie-1 (EC 2.7.10.1)TIE1 TIE 1138 Q15363 TMED2_HUMAN Transmembrane emp24 domain-containingprotein 2 (Membrane protein p24A) (p24) TMED2 RNP24 201 (p24 familyprotein beta-1) (p24beta1) Q7Z7H5 TMED4_HUMAN Transmembrane emp24domain-containing protein 4 (Endoplasmic reticulum stress- TMED4 ERS25227 response protein 25) (ERS25) (GMP25iso) (PutativeNF-kappa-B-activating protein 156) (p24 family protein alpha-3)(p24alpha3) Q9Y3B3 TMED7_HUMAN Transmembrane emp24 domain-containingprotein 7 (p24 family protein gamma-3) TMED7 CGI-109 224 (p24gamma3)(p27) Q07011 TNR9_HUMAN Tumor necrosis factor receptor superfamilymember 9 (4-1BB ligand receptor) (CDw137) TNFRSF9 CD137 255 (T-cellantigen 4-1BB homolog) (T-cell antigen ILA) (CD antigen CD137) ILAP01135 TGFA_HUMAN Protransforming growth factor alpha [Cleaved into:Transforming growth factor alpha TGFA 160 (TGF-alpha) (EGF-like TGF)(ETGF) (TGF type 1)] P37173 TGFR2_HUMAN TGF-beta receptor type-2(TGFR-2) (EC 2.7.11.30) (TGF-beta type II receptor) TGFBR2 567(Transforming growth factor-beta receptor type II) (TGF-beta receptortype II) (TbetaR-II) Q9UPZ6 THS7A_HUMAN Thrombospondin type-1domain-containing protein 7A THSD7A KIAA0960 1657 Q9C0I4 THS7B_HUMANThrombospondin type-1 domain-containing protein 7B THSD7B KIAA1679 1608Q96H15 TIMD4_HUMAN T-cell immunoglobulin and mucin domain-containingprotein 4 (TIMD-4) (T-cell TIMD4 TIM4 378 immunoglobulin mucin receptor4) (TIM-4) (T-cell membrane protein 4) Q15399 TLR1_HUMAN Toll-likereceptor 1 (Toll/interleukin-1 receptor-like protein) (TIL) (CD antigenCD281) TLR1 KIAA0012 786 O15455 TLR3_HUMAN Toll-like receptor 3 (CDantigen CD283) TLR3 904 O60602 TLR5_HUMAN Toll-like receptor 5(Toll/interleukin-1 receptor-like protein 3) TLR5 TIL3 858 Q4V9L6TM119_HUMAN Transmembrane protein 119 (Osteoblast induction factor)(OBIF) TMEM119 283 PSEC0199 UNQ731/PRO1415 Q13445 TMED1_HUMANTransmembrane emp24 domain-containing protein 1 (Interleukin-1receptor-like 1 ligand) TMED1 IL1RL1L 227 (Putative T1/ST2receptor-binding protein) (p24 family protein gamma-1) (Tp24) IL1RL1LG(p24gamma1) Q9Y3A6 TMED5_HUMAN Transmembrane emp24 domain-containingprotein 5 (p24 family protein gamma-2) TMED5 CGI-100 229 (p24gamma2)(p28) UNQ397/PRO733 P49755 TMEDA_HUMAN Transmembrane emp24domain-containing protein 10 (21 kDa transmembrane-trafficking TMED10TMP21 219 protein) (S31III125) (S31I125) (Tmp-21-I) (Transmembraneprotein Tmp21) (p23) (p24 family protein delta-1) (p24delta1) (p24delta)Q86V40 TIKI1_HUMAN Metalloprotease TIKI1 (EC 3.4.—.—) (TRABdomain-containing protein 2A) TRABD2A C2orf89 505 TIKI1 Q9Y2C9TLR6_HUMAN Toll-like receptor 6 (CD antigen CD286) TLR6 796 Q9NR97TLR8_HUMAN Toll-like receptor 8 (CD antigen CD288) TLR8 1041UNQ249/PRO286 Q8WZ59 TM190_HUMAN Transmembrane protein 190 TMEM190 MDAC1177 Q6UWW9 TM207_HUMAN Transmembrane protein 207 TMEM207 146UNQ846/PRO1784 Q9UK28 TM59L_HUMAN Transmembrane protein 59-like(Brain-specific membrane-anchored protein) TMEM59L BSMAP 342 C19orf4Q8WW62 TMED6_HUMAN Transmembrane emp24 domain-containing protein 6 (p24family protein gamma-5) TMED6 240 (p24gamma5) UNQ9146/PRO34237 Q9BVK6TMED9_HUMAN Transmembrane emp24 domain-containing protein 9 (GMP25)(Glycoprotein 25L2) (p24 TMED9 GP25L2 235 family protein alpha-2)(p24alpha2) (p25) O14668 TMG1_HUMAN Transmembrane gamma-carboxyglutamicacid protein 1 (Proline-rich gamma- PRRG1 PRGP1 218 carboxyglutamic acidprotein 1) (Proline-rich Gla protein 1) TMG1 Q96BF3 TMIG2_HUMANTransmembrane and immunoglobulin domain-containing protein 2 (CD28homolog) TMIGD2 CD28H 282 (Immunoglobulin and proline-rich receptor 1)(IGPR-1) IGPR1 UNQ3059/PRO9879 P43489 TNR4_HUMAN Tumor necrosis factorreceptor superfamily member 4 (ACT35 antigen) (OX40L receptor) TNFRSF4TXGP1L 277 (TAX transcriptionally-activated glycoprotein 1 receptor) (CDantigen CD134) P25942 TNR5_HUMAN Tumor necrosis factor receptorsuperfamily member 5 (B-cell surface antigen CD40) (Bp50) (CD40Lreceptor) CD40 TNFRSF5 277 (CDw40) (CD antigen CD40) P25445 TNR6_HUMANTumor necrosis factor receptor superfamily member 6 (Apo-1 antigen)(Apoptosis- FAS APT1 FAS1 335 mediating surface antigen FAS) (FASLGreceptor) (CD antigen CD95) TNFRSF6 O14763 TR10B_HUMAN Tumor necrosisfactor receptor superfamily member 10B (Death receptor 5) (TNF-relatedTNFRSF10B DR5 440 apoptosis-inducing ligand receptor 2) (TRAIL receptor2) (TRAIL-R2) (CD antigen CD262) KILLER TRAILR2 TRICK2 ZTNFR9UNQ160/PRO186 Q8TB96 TIP_HUMAN T-cell immunomodulatory protein (ProteinTIP) (Integrin-alpha FG-GAP repeat-containing ITFG1 LNKN-1 TIP 612protein 1) (Linkin) CDA08 O00206 TLR4_HUMAN Toll-like receptor 4 (hToll)(CD antigen CD284) TLR4 839 Q6P9G4 TM154_HUMAN Transmembrane protein 154TMEM154 183 Q9BXS4 TMM59_HUMAN Transmembrane protein 59 (Livermembrane-bound protein) TMEM59 C1orf8 323 HSPC001 UNQ169/PRO195 Q9NP84TNR12_HUMAN Tumor necrosis factor receptor superfamily member 12A(Fibroblast growth factor- TNFRSF12A FN14 129 inducible immediate-earlyresponse protein 14) (FGF-inducible 14) (Tweak-receptor) (TweakR) (CDantigen CD266) Q9Y5U5 TNR18_HUMAN Tumor necrosis factor receptorsuperfamily member 18 (Activation-inducible TNFR family TNFRSF18 AITR241 receptor) (Glucocorticoid-induced TNFR-related protein) (CD antigenCD357) GITR UNQ319/PRO364 P20333 TNR1B_HUMAN Tumor necrosis factorreceptor superfamily member 1B (Tumor necrosis factor receptor TNFRSF1BTNFBR 461 2) (TNF-R2) (Tumor necrosis factor receptor type II) (TNF-RII)(TNFR-II) (p75) (p80 TNF- TNFR2 alpha receptor) (CD antigen CD120b)(Etanercept) [Cleaved into: Tumor necrosis factor receptor superfamilymember 1b, membrane form; Tumor necrosis factor-binding protein 2(TBP-2) (TBPII)] Q9UBN6 TR10D_HUMAN Tumor necrosis factor receptorsuperfamily member 10D (Decoy receptor 2) (DcR2) TNFRSF10D DCR2 386(TNF-related apoptosis-inducing ligand receptor 4) (TRAIL receptor 4)(TRAIL-R4) TRAILR4 TRUNDD (TRAIL receptor with a truncated death domain)(CD antigen CD264) UNQ251/PRO288 Q9NZC2 TREM2_HUMAN Triggering receptorexpressed on myeloid cells 2 (TREM-2) (Triggering receptor TREM2 230expressed on monocytes 2) A6NFA1 TIKI2_HUMAN Metalloprotease TIKI2 (EC3.4.—.—) (Heart, kidney and adipose-enriched transmembrane proteinhomolog) TRABD2B HKAT 517 (TRAB domain-containing protein 2B) TIKI2Q9NYK1 TLR7_HUMAN Toll-like receptor 7 TLR7 1049 UNQ248/PRO285 Q9NR96TLR9_HUMAN Toll-like receptor 9 (CD antigen CD289) TLR9 1032UNQ5798/PRO19605 A2RRL7 TM213_HUMAN Transmembrane protein 213 TMEM213107 Q9P0T7 TMEM9_HUMAN Transmembrane protein 9 (Dermal papilla-derivedprotein 4) TMEM9 DERP4 183 TMEM9A HSPC186 PSEC0012 UNQ631/PRO1248 A2RUT3TMM89_HUMAN Transmembrane protein 89 TMEM89 159 Q9H3N1 TMX1_HUMANThioredoxin-related transmembrane protein 1 (Thioredoxindomain-containing protein 1) TMX1 TMX TXNDC 280 (TransmembraneTrx-related protein) TXNDC1 PSEC0085 UNQ235/PRO268 Q92956 TNR14_HUMANTumor necrosis factor receptor superfamily member 14 (Herpes virus entrymediator A) TNFRSF14 HVEA 283 (Herpesvirus entry mediator A) (HveA)(Tumor necrosis factor receptor-like 2) (TR2) (CD antigen CD270) HVEMUNQ329/PRO509 Q9NS68 TNR19_HUMAN Tumor necrosis factor receptorsuperfamily member 19 (TRADE) (Toxicity and JNK inducer) TNFRSF19 TAJ423 TROY UNQ1888/PRO4333 P19438 TNR1A_HUMAN Tumor necrosis factorreceptor superfamily member 1A (Tumor necrosis factor receptor TNFRSF1ATNFAR 455 1) (TNF-R1) (Tumor necrosis factor receptor type I) (TNF-RI)(TNFR-I) (p55) (p60) (CD TNFR1 antigen CD120a) [Cleaved into: Tumornecrosis factor receptor superfamily member 1A, membrane form; Tumornecrosis factor-binding protein 1 (TBPI)] Q93038 TNR25_HUMAN Tumornecrosis factor receptor superfamily member 25 (Apo-3)(Apoptosis-inducing TNFRSF25 APO3 417 receptor AIR) (Apoptosis-mediatingreceptor DR3) (Apoptosis-mediating receptor DDR3 DR3 TRAMP) (Deathreceptor 3) (Lymphocyte-associated receptor of death) (LARD) (ProteinTNFRSF12 WSL WSL) (Protein WSL-1) WSL1 UNQ455/PRO779 P0DKB5 TPBGL_HUMANTrophoblast glycoprotein-like TPBGL 382 Q9BX59 TPSNR_HUMANTapasin-related protein (TAPASIN-R) (TAP-binding protein-like)(TAP-binding protein- TAPBPL 468 related protein) (TAPBP-R)(Tapasin-like) O60603 TLR2_HUMAN Toll-like receptor 2(Toll/interleukin-1 receptor-like protein 4) (CD antigen CD282) TLR2TIL4 784 Q6UXF1 TM108_HUMAN Transmembrane protein 108 TMEM108 575KIAA1690 UNQ1875/PRO4318 Q8IV31 TM139_HUMAN Transmembrane protein 139TMEM139 216 UNQ1932/PRO4407 A6NLX4 TM210_HUMAN Transmembrane protein 210TMEM210 147 Q9Y3Q3 TMED3_HUMAN Transmembrane emp24 domain-containingprotein 3 (Membrane protein p24B) (p24 TMED3 C15orf22 217 family proteingamma-4) (p24gamma4) (p26) UNQ5357/PRO1078 O14669 TMG2_HUMANTransmembrane gamma-carboxyglutamic acid protein 2 (Praline-rich gamma-PRRG2 PRGP2 202 carboxyglutamic acid protein 2) (Proline-rich Glaprotein 2) TMG2 Q9BZD7 TMG3_HUMAN Transmembrane gamma-carboxyglutamicacid protein 3 (Proline-rich gamma- PRRG3 PRGP3 231 carboxyglutamic acidprotein 3) (Proline-rich Gla protein 3) TMG3 Q9Y320 TMX2_HUMANThioredoxin-related transmembrane protein 2 (Cell proliferation-inducinggene 26 protein) TMX2 TXNDC14 296 (Thioredoxin domain-containing protein14) CGI-31 My009 PIG26 PSEC0045 UNQ237/PRO270 P36941 TNR3_HUMAN Tumornecrosis factor receptor superfamily member 3 (Lymphotoxin-betareceptor) LTBR D12S370 435 (Tumor necrosis factor C receptor) (Tumornecrosis factor receptor 2-related protein) TNFCR TNFR3 (Tumor necrosisfactor receptor type III) (TNF-RIII) (TNFR-III) TNFRSF3 Q13641TPBG_HUMAN Trophoblast glycoprotein (5T4 oncofetal antigen) (5T4oncofetal trophoblast glycoprotein) TPBG 5T4 420 (5T4 oncotrophoblastglycoprotein) (M6P1) (Wnt-activated inhibitory factor 1) (WAIF1) P40238TPOR_HUMAN Thrombopoietin receptor (TPO-R) (Myeloproliferative leukemiaprotein) (Proto-oncogene MPL TPOR 635 c-MpI) (CD antigen CD110) P07204TRBM_HUMAN Thrombomodulin (TM) (Fetomodulin) (CD antigen CD141) THBDTHRM 575 Q5T2D2 TRML2_HUMAN Trem-like transcript 2 protein (TLT-2)(Triggering receptor expressed on myeloid cells-like TREML2 C6orf76 321protein 2) TLT2 UNQ6268/PRO20473 Q6UXZ0 TMIG1_HUMAN Transmembrane andimmunoglobulin domain-containing protein 1 TMIGD1 TMIGD 262UNQ9372/PRO34164 Q86YD3 TMM25_HUMAN Transmembrane protein 25 TMEM25 366UNQ2531/PRO6030 Q6P7N7 TMM81_HUMAN Transmembrane protein 81 TMEM81 255UNQ2788/PRO7178 Q3KNT9 TMM95_HUMAN Transmembrane protein 95 TMEM95 176UNQ9390/PRO34281 Q9H1E5 TMX4_HUMAN Thioredoxin-related transmembraneprotein 4 (Thioredoxin domain-containing protein 13) TMX4 KIAA1162 349TXNDC13 PSEC0095 UNQ475/PRO938 Q9Y6Q6 TNR11_HUMAN Tumor necrosis factorreceptor superfamily member 11A (Osteoclast differentiation factorTNFRSF11A RANK 616 receptor) (ODFR) (Receptor activator of NF-KB) (CDantigen CD265) Q86YW5 TRML1_HUMAN Trem-like transcript 1 protein (TLT-1)(Triggering receptor expressed on myeloid cells-like TREML1 TLT1 311protein 1) UNQ1825/PRO3438 P08138 TNR16_HUMAN Tumor necrosis factorreceptor superfamily member 16 (Gp80-LNGFR) (Low affinity NGFR TNFRSF16427 neurotrophin receptor p75NTR) (Low-affinity nerve growth factorreceptor) (NGF receptor) (P75 ICD) (CD antigen CD271) O75509 TNR21_HUMANTumor necrosis factor receptor superfamily member 21 (Death receptor 6)(CD antigen CD358) TNFRSF21 DR6 655 UNQ437/PRO868 P28908 TNR8_HUMANTumor necrosis factor receptor superfamily member 8 (CD30L receptor)(Ki-1 antigen) TNFRSF8 CD30 595 (Lymphocyte activation antigen CD30) (CDantigen CD30) D1S166E O00220 TR10A_HUMAN Tumor necrosis factor receptorsuperfamily member 10A (Death receptor 4) (TNF-related TNFRSF10A APO2468 apoptosis-inducing ligand receptor 1) (TRAIL receptor 1) (TRAIL-R1)(CD antigen CD261) DR4 TRAILR1 Q9NP99 TREM1_HUMAN Triggering receptorexpressed on myeloid cells 1 (TREM-1) (Triggering receptor TREM1 234expressed on monocytes 1) (CD antigen CD354) O15533 TPSN_HUMAN Tapasin(TPN) (TPSN) (NGS-17) (TAP-associated protein) (TAP-binding protein)TAPBP NGS17 448 TAPA Q969Z4 TR19L_HUMAN Tumor necrosis factor receptorsuperfamily member 19L (Receptor expressed in RELT TNFRSF19L 430lymphoid tissues) Q7L0X0 TRIL_HUMAN TLR4 interactor with leucine richrepeats (Leucine-rich repeat-containing protein KIAA0644) TRIL KIAA0644811 Q5BVD1 TTMP_HUMAN TPA-induced transmembrane protein TTMP C3orf52 217Q96J42 TXD15_HUMAN Thioredoxin domain-containing protein 15 TXNDC15C5orf14 360 UNQ335/PRO534 Q9P2J2 TUTLA_HUMAN Protein turtle homolog A(Immunoglobulin superfamily member 9A) (IgSF9A) IGSF9 IGSF9A 1179KIAA1355 NRT1 Q9UPX0 TUTLB_HUMAN Protein turtle homolog B(Immunoglobulin superfamily member 9B) (IgSF9B) IGSF9B KIAA1030 1349Q3SY77 UD3A2_HUMAN UDP-glucuronosyltransferase 3A2 (UDPGT 3A2) (EC2.4.1.17) UGT3A2 PSEC0073 523 UNQ842/PRO1780 P14679 TYRO_HUMANTyrosinase (EC 1.14.18.1) (LB24-AB) (Monophenol monooxygenase) (SK29-AB)(Tumor rejection antigen AB) TYR 529 P40126 TYRP2_HUMAN L-dopachrometautomerase (DCT) (DT) (EC 5.3.3.12) (L-dopachrome Delta-isomerase) DCTTYRP2 519 (Tyrosinase-related protein 2) (TRP-2) (TRP2) O95185UNC5C_HUMAN Netrin receptor UNC5C (Protein unc-5 homolog 3) (Proteinunc-5 homolog C) UNC5C UNC5H3 931 Q06418 TYRO3_HUMAN Tyrosine-proteinkinase receptor TYRO3 (EC 2.7.10.1) (Tyrosine-protein kinase BYK) TYRO3BYK DTK 890 (Tyrosine-protein kinase DTK) (Tyrosine-protein kinase RSE)(Tyrosine-protein kinase RSE SKY TIF SKY) (Tyrosine-protein kinase TIF)Q9Y4X1 UD2A1_HUMAN UDP-glucuronosyltransferase 2A1 (UDPGT 2A1) (EC2.4.1.17) UGT2A1 UGT2A2 527 Q9BT76 UPK3B_HUMAN Uroplakin-3b (UP3b)(Uroplakin IIIb) (UPIIIb) (p35) UPK3B 320 O43914 TYOBP_HUMAN TYROprotein tyrosine kinase-binding protein (DNAX-activation protein 12)(Killer- TYROBP DAP12 113 activating receptor-associated protein)(KAR-associated protein) KARAP Q6NUS8 UD3A1_HUMANUDP-glucuronosyltransferase 3A1 (UDPGT 3A1) (EC 2.4.1.17) UGT3A1 523O00526 UPK2_HUMAN Uroplakin-2 (UP2) (Uroplakin II) (UPII) UPK2 184B0FP48 UPK3L_HUMAN Uroplakin-3b-like protein UPK3BL UPLP 263 P17643TYRP1_HUMAN 5,6-dihydroxyindole-2-carboxylicacid oxidase (DHICA oxidase)(EC 1.14.18.—) (Catalase TYRP1 CAS2 TYRP 537 B) (Glycoprotein 75)(Melanoma antigen gp75) (Tyrosinase-related protein 1) (TRP) (TRP-1)(TRP1) TYRRP O75631 UPK3A_HUMAN Uroplakin-3a (UP3a) (Uroplakin III)(UPIII) UPK3A UPK3 287 O75445 USH2A_HUMAN Usherin (Usher syndrome typeIIa protein) (Usher syndrome type-2A protein) USH2A 5202 P30530UFO_HUMAN Tyrosine-protein kinase receptor UFO (EC 2.7.10.1) (AXLoncogene) AXL UFO 894 Q8IZJ1 UNC5B_HUMAN Netrin receptor UNC5B (Proteinunc-5 homolog 2) (Protein unc-5 homolog B) (p53- UNC5B P53RDL1 945regulated receptor for death and life protein 1) (p53RDL1) UNC5H2UNQ1883/PRO4326 Q6UWM9 UD2A3_HUMAN UDP-glucuronosyltransferase 2A3(UDPGT 2A3) (EC 2.4.1.17) UGT2A3 527 UNQ2559/PRO6239 Q5DID0 UROL1_HUMANUromodulin-like 1 (Olfactorin) UMODL1 1318 Q6ZN44 UNC5A_HUMAN Netrinreceptor UNC5A (Protein unc-5 homolog 1) (Protein unc-5 homolog A) UNC5AKIAA1976 842 UNC5H1 Q6UXZ4 UNC5D_HUMAN Netrin receptor UNC5D (Proteinunc-5 homolog 4) (Protein unc-5 homolog D) UNC5D KIAA1777 953 UNC5H4UNQ6012/PRO34692 P19320 VCAM1_HUMAN Vascular cell adhesion protein 1(V-CAM 1) (VCAM-1) (INCAM-100) (CD antigen CD106) VCAM1 L1CAM 739 P35916VGFR3_HUMAN Vascular endothelial growth factor receptor 3 (VEGFR-3) (EC2.7.10.1) (Fms-like tyrosine FLT4 VEGFR3 1363 kinase 4) (FLT-4)(Tyrosine-protein kinase receptor FLT4) Q7Z7D3 VTCN1_HUMAN V-setdomain-containing T-cell activation inhibitor 1 (B7 homolog 4) (B7-H4)(B7h.5) VTCN1 B7H4 282 (Immune costimulatory protein B7-H4) (ProteinB7S1) (T-cell costimulatory molecule B7x) UNQ659/PRO1291 Q6EMK4VASN_HUMAN Vasorin (Protein slit-like 2) VASN SLITL2 673 UNQ314/PRO357/PRO1282 Q96AW1 VOPP1_HUMAN Vesicular, overexpressed in cancer,prosurvival protein 1 (EGFR-coamplified and VOPP1 ECOP 172 overexpressedprotein) (ECop) (Glioblastoma-amplified secreted protein) (Putative NF-GASP kappa-B-activating protein 055N) P17948 VGFR1_HUMAN Vascularendothelial growth factor receptor 1 (VEGFR-1) (EC 2.7.10.1) (Fms-liketyrosine FLT1 FLT FRT 1338 kinase 1) (FLT-1) (Tyrosine-protein kinaseFRT) (Tyrosine-protein kinase receptor FLT) VEGFR1 (FLT) (Vascularpermeability factor receptor) Q9H7M9 VISTA_HUMAN V-type immunoglobulindomain-containing suppressor of T-cell activation (Platelet C10orf54SISP1 311 receptor Gi24) (Stress-induced secreted protein-1) (Sisp-1)(V-set domain-containing VISTA PP2135 immunoregulatory receptor)UNQ730/PRO1412 Q86VR7 VS10L_HUMAN V-set and immunoglobulindomain-containing protein 10-like VSIG10L 867 Q96IQ7 VSIG2_HUMAN V-setand immunoglobulin domain-containing protein 2 (Cortical thymocyte-likeprotein) VSIG2 CTH CTXL 327 (CT-like protein) UNQ2770/PRO7154 Q5VU13VSIG8_HUMAN V-set and immunoglobulin domain-containing protein 8 VSIG8C1orf204 414 P78423 X3CL1_HUMAN Fractalkine (C-X3-C motif chemokine 1)(CX3C membrane-anchored chemokine) CX3CL1 FKN NTT 397 (Neurotactin)(Small-inducible cytokine D1) [Cleaved into: Processed fractalkine]SCYD1 A-152E5.2 P35968 VGFR2_HUMAN Vascular endothelial growth factorreceptor 2 (VEGFR-2) (EC 2.7.10.1) (Fetal liver kinase KDR FLK1 VEGFR21356 1) (FLK-1) (Kinase insert domain receptor) (KDR) (Protein-tyrosinekinase receptor flk-1) (CD antigen CD309) Q8N0Z9 VSI10_HUMAN V-set andimmunoglobulin domain-containing protein 10 VSIG10 540 Q8IW00VSTM4_HUMAN V-set and transmembrane domain-containing protein 4 [Cleavedinto: Peptide Lv] VSTM4 C10orf72 320 P55808 XG_HUMAN Glycoprotein Xg(Protein PBDX) XG PBDX 180 P98155 VLDLR_HUMAN Very low-densitylipoprotein receptor (VLDL receptor) (VLDL-R) VLDLR 873 Q86XK7VSIG1_HUMAN V-set and immunoglobulin domain-containing protein 1 (Cellsurface A33 antigen) VSIG1 GPA34 387 (Glycoprotein A34) Q9Y279VSIG4_HUMAN V-set and immunoglobulin domain-containing protein 4(Protein Z39Ig) VSIG4 CRIg Z39IG 399 UNQ317/PRO362 A6NLU5 VTM2B_HUMANV-set and transmembrane domain-containing protein 2B VSTM2B 285 A8MXK1VSTM5_HUMAN V-set and transmembrane domain-containing protein 5 VSTM5C11orf90 200 Q8N1Y9 YI025_HUMAN Putative uncharacterized proteinFLJ37218 231 P60852 ZP1_HUMAN Zona pellucida sperm-binding protein 1(Zona pellucida glycoprotein 1) (Zp-1) [Cleaved ZP1 638 into: Processedzona pellucida sperm-binding protein 1] Q05996 ZP2_HUMAN Zona pellucidasperm-binding protein 2 (Zona pellucida glycoprotein 2) (Zp-2) (Zona ZP2ZPA 745 pellucida protein A) [Cleaved into: Processed zona pellucidasperm-binding protein 2] Q9Y493 ZAN_HUMAN Zonadhesin ZAN 2812 Q9ULT6ZNRF3_HUMAN E3 ubiquitin-protein ligase ZNRF3 (EC 6.3.2.—) (RING fingerprotein 203) (Zinc/RING ZNRF3 KIAA1133 936 finger protein 3) RNF203Q8TCW7 ZPLD1_HUMAN Zona pellucida-like domain-containing protein 1 (ZPdomain-containing protein 1) ZPLD1 415 Q8WWF5 ZNRF4_HUMAN E3ubiquitin-protein ligase ZNRF4 (EC 6.3.2.—) (Nixin) (RING finger protein204) ZNRF4 RNF204 429 (Zinc/RING finger protein 4) P21754 ZP3_HUMAN Zonapellucida sperm-binding protein 3 (Sperm receptor) (ZP3A/ZP3B) (Zonapellucida ZP3 ZP3A ZP3B 424 glycoprotein 3) (Zp-3) (Zona pellucidaprotein C) [Cleaved into: Processed zona pellucida ZPC sperm-bindingprotein 3] Q12836 ZP4_HUMAN Zona pellucida sperm-binding protein 4 (Zonapellucida glycoprotein 4) (Zp-4) (Zona ZP4 ZPB 540 pellucida protein B)[Cleaved into: Processed zona pellucida sperm-binding protein 4] K9MUJ5K9MUJ5_HUMAN Toll-like receptor 4 (Fragment) TLR4 138 K9MUQ3K9MUQ3_HUMAN Toll-like receptor 4 (Fragment) TLR4 138 D3DNA1D3DNA1_HUMAN Integrin beta ITGB5 hCG_17803 691 K9MTL8 K9MTL8_HUMANToll-like receptor 4 (Fragment) TLR4 138 K9MSZ3 K9MSZ3_HUMAN Toll-likereceptor 4 (Fragment) TLR4 138 K9MT91 K9MT91_HUMAN Toll-like receptor 4(Fragment) TLR4 138 D3DSM0 D3DSM0_HUMAN Integrin beta ITGB2 hCG_401305712 K9MT22 K9MT22_HUMAN Toll-like receptor 4 (Fragment) TLR4 138 K9MUK7K9MUK7_HUMAN Toll-like receptor 4 (Fragment) TLR4 138 D0EWT7D0EWT7_HUMAN Toll-like receptor 4 (Fragment) TLR-4 TLR4 169 G3V1J9G3V1J9_HUMAN Transmembrane emp24 domain-containing protein 3(Transmembrane emp24 protein TMED3 hCG_24828 146 transport domaincontaining 3, isoform CRA_b) L7RT22 L7RT22_HUMAN Integrin beta ITGB5 799G3V1W8 G3V1W8_HUMAN Serine/threonine-protein kinase receptor (EC2.7.11.30) ACVRL1 517 hCG_37967 A3QNQ0 A3QNQ0_HUMAN TGF-beta receptortype-2 (TGFR-2) (EC 2.7.11.30) (TGF-beta type II receptor) TGFBR2 567(Transforming growth factor-beta receptor type II) hCG_1997782 B4E1S6B4E1S6_HUMAN Syndecan SDC4 hCG_38363 126 A0A024R8T0 A0A024R8T0_HUMANIntegrin beta ITGB4 hCG_27538 1822 D3DPA4 D3DPA4_HUMANSerine/threonine-protein kinase receptor (EC 2.7.11.30) ACVR1 509hCG_1811747 A0A024R6I3 A0A024R6I3_HUMAN Testicular tissue protein Li 206(Transmembrane emp24-like trafficking protein 10 TMED10 219 (Yeast),isoform CRA_a) hCG_22348 A0A024RB01 A0A024RB01_HUMAN Integrin, alpha 5(Fibronectin receptor, alpha polypeptide), isoform CRA_b ITGA5 hCG_219391098 A0A024R7M0 A0A024R7M0_HUMAN Transmembrane emp24 protein transportdomain containing 9, isoform CRA_a TMED9 hCG_41592 235 B7Z4L4B7Z4L4_HUMAN Dolichyl-diphosphooligosaccharide--proteinglycosyltransferase subunit 1 (EC 2.4.99.18) RPN1 435 A0A024DBF0A0A024DBF0_HUMAN Integrin beta (Fragment) ITGB2 80 A0A024RDA0A0A024RDA0_HUMAN V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogenehomolog, isoform CRA_a KIT hCG_22160 976 Q9BUG9 Q9BUG9_HUMAN Integrinbeta ITGB8 hCG_37311 439 D3DPN2 D3DPN2_HUMAN Syndecan SDC3 hCG_15913 384A0A024RC30 A0A024RC30_HUMAN Desmoglein 3 (Pemphigus vulgaris antigen),isoform CRA_a DSG3 hCG_25473 999 E9PBI9 E9PBI9_HUMAN Syndecan SDC2 172A0A024RC29 A0A024RC29_HUMAN Desmocollin 3, isoform CRA_b DSC3 896hCG_2022649 X5D8X5 X5D8X5_HUMAN Cadherin 10 type 2 isoform A (Cadherin10, type 2 (T2-cadherin)) (Fragment) CDH10 hCG_36812 788 B2R627B2R627_HUMAN cDNA, FLJ92752, highly similar to Homo sapiens integrin,alpha 5 (fibronectin receptor, 1049 alphapolypeptide) (ITGA5), mRNAQ6FHT8 Q6FHT8_HUMAN RNP24 protein (Transmembrane emp24 domaintrafficking protein 2, isoform CRA_a) RNP24 TMED2 201 (cDNA, FLJ93436,Homo sapiens coated vesicle membrane protein (RNP24), mRNA) hCG_1743563B4DTY8 B4DTY8_HUMAN cDNA FLJ61587, highly similar to Integrin alpha-1(Fragment) 1173 Q96CZ9 Q96CZ9_HUMAN Cadherin 11, type 2, OB-cadherin(Osteoblast) (Cadherin 11, type 2, OB-cadherin CDH11 hCG_26636 796(Osteoblast), isoform CRA_c) A0A024RD88 A0A024RD88_HUMAN Kinase insertdomain receptor (A type III receptor tyrosine kinase), isoform CRA_a KDRhCG_31572 1356 A0A024R8N2 A0A024R8N2_HUMAN Integrin beta ITGB4 hCG_275381875 A0A024R2B2 A0A024R2B2_HUMAN Cadherin 7, type 2, isoform CRA_a CDH7hCG_32903 785 E7EQW5 E7EQW5_HUMAN Integrin beta (Fragment) ITGB1 163Q59F03 Q59F03_HUMAN Integrin alpha 3 isoform b, variant (Fragment) 749A0A0G2JRA4 A0A0G2JRA4_HUMAN Cadherin-4 (Fragment) CDH4 566 U3KQ84U3KQ84_HUMAN Dolichyl-diphosphooligosaccharide--proteinglycosyltransferase 48 kDa subunit DDOST 155 (Oligosaccharyl transferase48 kDa subunit) (EC 2.4.99.18) (Fragment) B4E2C1 B4E2C1_HUMAN cDNAFLJ57776, highly similar to Transmembrane emp24 domain-containingprotein 7 136 J3KRI5 J3KRI5_HUMAN Cadherin-8 CDH8 744 E9PD35E9PD35_HUMAN Vascular endothelial growth factor receptor 3 FLT4 1306E7EQ72 E7EQ72_HUMAN Transmembrane emp24 domain-containing protein 2(Fragment) TMED2 166 D2JYI3 D2JYI3_HUMAN Toll-like receptor 4 (Fragment)TLR4 121 J3KT08 J3KT08_HUMAN Uncharacterized protein (Fragment) 172A8K0L1 A8K0L1_HUMAN cDNA FLJ77485, highly similar to Homo sapienscadherin-like 24 (CDH24), transcript 781 variant 2, mRNA D2JYI2D2JYI2_HUMAN Toll-like receptor 4 (Fragment) TLR4 122 E7EP60E7EP60_HUMAN Integrin alpha-4 (Fragment) ITGA4 614 Q59H01 Q59H01_HUMANProtocadherin gamma subfamily A, 7 isoform 1 variant (Fragment) 895D2JYI5 D2JYI5_HUMAN Toll-like receptor 4 (Fragment) TLR4 124 J3KNV4J3KNV4_HUMAN Integrin alpha-7 ITGA7 1131 H3BM21 H3BM21_HUMAN Integrinbeta (Fragment) 787 B4DN28 B4DN28_HUMAN cDNA FLJ54639, highly similar toIntegrin alpha-8 (Fragment) 1048 A0A0S2Z4U3 A0A0S2Z4U3_HUMAN Syndecan(Fragment) SDC3 370 B4DL99 B4DL99_HUMANDolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1(EC 2.4.99.18) 581 B4DLF0 B4DLF0_HUMAN cDNA FLJ50795, highly similar toCadherin-3 774 Q6P4R2 Q6P4R2_HUMAN Protocadherin alpha subfamily C, 2PCDHAC2 1007 V9GYZ1 V9GYZ1_HUMAN Integrin beta (Fragment) ITGB5 139D1CS55 D1CS55_HUMAN Toll-like receptor 4 TLR4 839 D0EWT8 D0EWT8_HUMANToll-like receptor 4 (Fragment) TLR-4 TLR4 169 A8K2C5 A8K2C5_HUMAN cDNAFLJ78159, highly similar to Homo sapiens cadherin 20, type 2 (CDH20),mRNA 801 Q59GD1 Q59GD1_HUMAN Protocadherin gamma subfamily A, 6 isoform1 variant (Fragment) 950 L7RSL3 L7RSL3_HUMAN Fms-related tyrosine kinase1 (Vascular endothelial growth factor/vascular permeability FLT1 1338factor receptor) A8K8T0 A8K8T0_HUMAN cDNA FLJ78760, highly similar toHomo sapiens integrin, alpha 11 (ITGA11), transcript 1188 variant 1,mRNA Q4VAU9 Q4VAU9_HUMAN Serine/threonine-protein kinase receptor (EC2.7.11.30) ACVR2B 303 Q5T3E5 Q5T3E5_HUMAN Integrin beta (Fragment) ITGB189 E5RK25 E5RK25_HUMAN Integrin beta (Fragment) ITGB2 160 A8KAM8A8KAM8_HUMAN Platelet-derived growth factor receptor beta (PDGF-R-beta)(PDGFR-beta) (EC 2.7.10.1) 1106 (Beta platelet-derived growth factorreceptor) (Beta-type platelet-derived growth factor receptor) E9PQJ2E9PQJ2_HUMAN Integrin beta (Fragment) ITGB1 104 B4E2S6 B4E2S6_HUMANSerine/threonine-protein kinase receptor (EC 2.7.11.30) 397 A0A087WXP3A0A087WXP3_HUMAN Integrin beta ITGB6 693 A8K0L9 A8K0L9_HUMAN cDNAFLJ76999, highly similar to Homo sapiens cadherin-like 22 (CDH22), mRNA828 D2JYI1 D2JYI1_HUMAN TGF-beta receptor type-2 (TGFR-2) (EC 2.7.11.30)(TGF-beta type II receptor) TGFBR2 592 (Transforming growth factor-betareceptor type II) B7ZLD8 B7ZLD8_HUMAN Integrin beta ITGB4 1752 L7UW06L7UW06_HUMAN Integrin beta ITGB3 470 B4E3M0 B4E3M0_HUMAN cDNA FLJ58807,highly similar to Integrin alpha-11 650 B4DNJ5 B4DNJ5_HUMANDolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1(EC 2.4.99.18) 378 Q96HX3 Q96HX3_HUMANDolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1(EC 2.4.99.18) 568 (Fragment) X5DNG6 X5DNG6_HUMAN Cadherin 10 type 2isoform B (Fragment) CDH10 786 B7Z5H2 B7Z5H2_HUMAN Syndecan 172 F8VNX4F8VNX4_HUMAN Integrin beta (Fragment) ITGB7 158 B4DPP4 B4DPP4_HUMAN cDNAFLJ56646, highly similar to Transmembrane emp24 domain-containingprotein 9 121 B2RCN5 B2RCN5_HUMAN cDNA, FLJ96176, highly similar to Homosapiens cadherin 4, type 1, R-cadherin (retinal) 916 (CDH4), mRNA G3V2K7G3V2K7_HUMAN Transmembrane emp24 domain-containing protein 10 TMED10 153A8K6T3 A8K6T3_HUMAN cDNA FLJ78674, highly similar to Homo sapiensdesmocollin type 4 896 E9PLR6 E9PLR6_HUMAN Integrin beta (Fragment)ITGB1 143 D3XNU5 D3XNU5_HUMAN E-cadherin 1 CDH1 882 B4E2A1 B4E2A1_HUMANcDNA FLJ54402, highly similar to Integrin alpha-10 1095 C9JPK5C9JPK5_HUMAN Integrin beta (Fragment) ITGB1 98 B2R8A2 B2R8A2_HUMAN cDNA,FLJ93804, highly similar to Homo sapiens gp25L2 protein (HSGP25L2G),mRNA 214 L7UUZ7 L7UUZ7_HUMAN Integrin beta ITGB3 788 Q53EP4 Q53EP4_HUMANDolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1(EC 2.4.99.18) (Fragment) 607 Q59H32 Q59H32_HUMAN Protocadherin gammasubfamily A, 3 isoform 1 variant (Fragment) 961 K9MUK4 K9MUK4_HUMANToll-like receptor 4 (Fragment) TLR4 138 B3KMS6 B3KMS6_HUMAN cDNAFLJ12486 fis, clone NT2RM2000566, highly similar to Integrin alpha-7 973B4E045 B4E045_HUMAN cDNA FLJ59131, highly similar to Integrin alpha-4174 B7ZLD5 B7ZLD5_HUMAN Integrin beta ITGB4 1752 Q59EA3 Q59EA3_HUMANCadherin 5, type 2 preproprotein variant (Fragment) 807 E7ESK6E7ESK6_HUMAN Syndecan SDC2 165 B4DTP0 B4DTP0_HUMAN cDNA FLJ51087, highlysimilar to Cadherin-5 525 B4E3N0 B4E3N0_HUMAN Integrin beta 628 A7U833A7U833_HUMAN Integrin beta (Fragment) ITGB3 65 A0A024R8K7A0A024R8K7_HUMAN Integrin beta ITGB4 hCG_27538 1752 H7C580 H7C580_HUMANIntegrin beta (Fragment) ITGB5 79 H0YA32 H0YA32_HUMAN Integrin alpha-3(Fragment) ITGA3 84 Q59H14 Q59H14_HUMAN PREDICTED: integrin, alpha Dvariant (Fragment) 1177 E9PDS3 E9PDS3_HUMAN Integrin alpha-9 ITGA9 632B2R6U9 B2R6U9_HUMAN Delta-like protein 1218 B4E0R1 B4E0R1_HUMAN Integrinbeta 700 A5YM53 A5YM53_HUMAN ITGAV protein ITGAV 1048 Q6IBR0Q6IBR0_HUMAN Dolichyl-diphosphooligosaccharide--proteinglycosyltransferase subunit 1 (EC 2.4.99.18) RPN1 607 B4DP27B4DP27_HUMAN cDNA FLJ52153, highly similar to Transmembrane emp24domain-containing protein 2 169 A0A0U2ZQU7 A0A0U2ZQU7_HUMAN E-cadherin 1CDH1 882 B4DYQ7 B4DYQ7_HUMAN cDNA FLJ57822, highly similar to Integrinalpha-V 482 B2RAL6 B2RAL6_HUMAN cDNA, FLJ94991, highly similar to Homosapiens integrin, alpha L (antigen CD11A 1170 (p180), lymphocytefunction-associated antigen 1; alpha polypeptide) (ITGAL), mRNA E7ERX5E7ERX5_HUMAN Integrin beta (Fragment) ITGB1 125 F8WF32 F8WF32_HUMANDolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1(EC 2.4.99.18) RPN1 121 B4E0Q2 B4E0Q2_HUMAN cDNA FLJ60208, highlysimilar to Integrin alpha-4 366 B4DDT0 B4DDT0_HUMAN cDNA FLJ59664,highly similar to Integrin alpha-3 294 B7Z769 B7Z769_HUMAN Integrin beta228 E9PEE8 E9PEE8_HUMAN Integrin beta ITGB6 746 H7C4W1 H7C4W1_HUMANIntegrin beta (Fragment) ITGB5 263 E9PB77 E9PB77_HUMAN Integrin alpha-2ITGA2 641 B7Z8B0 B7Z8B0_HUMAN cDNA FLJ50317, highly similar to Integrinalpha-IIb 219 D6RA20 D6RA20_HUMAN Protocadherin alpha-4 PCDHA4 901Q5T3E6 Q5T3E6_HUMAN Integrin beta (Fragment) ITGB1 136 B4DQ56B4DQ56_HUMAN Syndecan 192 C9JA99 C9JA99_HUMAN Protocadherin alpha-13PCDHA13 904 Q9UII7 Q9UII7_HUMAN E-cadherin 901 B3KRT0 B3KRT0_HUMAN cDNAFLJ34857 fis, clone NT2NE2012533, highly similar to Cadherin-12 404Q8N6H6 Q8N6H6_HUMAN ITGA9 protein 632 A0A0B5HR54 A0A0B5HR54_HUMANSerine/threonine-protein kinase receptor (EC 2.7.11.30) 509 C9JXX7C9JXX7_HUMAN Integrin alpha-6 (Fragment) ITGA6 231 B4DLJ5 B4DLJ5_HUMANcDNA FLJ55716, highly similar to Desmocollin-2 912 V9GZ57 V9GZ57_HUMANIntegrin beta (Fragment) ITGB5 324 Q4LE35 Q4LE35_HUMAN ITGA7 variantprotein (Fragment) ITGA7 variant 1200 protein B4DIN4 B4DIN4_HUMANSyndecan 346 J3KNI6 J3KNI6_HUMAN Integrin beta (Fragment) ITGB2 322A8K2P8 A8K2P8_HUMAN cDNA FLJ76245, highly similar to Homo sapiensdesmocollin 2 (DSC2), transcript variant 901 Dsc2a, mRNA B4DLU2B4DLU2_HUMAN cDNA FLJ56496, highly similar to Integrin alpha-IIb 521F5H4M7 F5H4M7_HUMAN Transmembrane emp24 domain-containing protein 3TMED3 155 D0EWT9 D0EWT9_HUMAN Toll-like receptor 4 (Fragment) TLR-4 TLR4169 Q6PJE7 Q6PJE7_HUMAN ITGA4 protein (Fragment) ITGA4 617 E7ESP4E7ESP4_HUMAN Integrin alpha-2 ITGA2 942 B4E277 B4E277_HUMAN cDNAFLJ58873, highly similar to Transmembrane emp24 domain-containingprotein 3 155 B4DU18 B4DU18_HUMAN cDNA FLJ51093, highly similar toCadherin-5 750 B2R9J8 B2R9J8_HUMAN cDNA, FLJ94427, highly similar toHomo sapiens cadherin 20, type 2 (CDH20), mRNA 801 B4E282 B4E282_HUMANcDNA FLJ52401, highly similar to Integrin alpha-10 1036 F5H6T4F5H6T4_HUMAN Integrin beta ITGB7 471 G3V2Y2 G3V2Y2_HUMAN Transmembraneemp24 domain-containing protein 7 (Fragment) TMED7 82 B4DDR7B4DDR7_HUMAN cDNA FLJ54845, highly similar to Transmembrane emp24domain-containing protein 5 178 A0A087WT05 A0A087WT05_HUMANProtocadherin gamma-A4 PCDHGA4 962 B4DMA7 B4DMA7_HUMAN cDNA FLJ58514,highly similar to Cadherin-11 779 A0A0U2N547 A0A0U2N547_HUMAN Mast/stemcell growth factor receptor Kit isoform 3 (EC 2.7.10.1) KIT 971 B2R9L8B2R9L8_HUMAN Delta-like protein 685 E7EVZ9 E7EVZ9_HUMAN Integrin beta(Fragment) ITGB2 166 B4E2B8 B4E2B8_HUMAN Integrin beta 746 F5GX39F5GX39_HUMAN Transmembrane emp24 domain-containing protein 2 TMED2 116Q2VP98 Q2VP98_HUMAN Integrin beta (Fragment) ITGB4 644 A0A0S2Z310A0A0S2Z310_HUMAN Serine/threonine-protein kinase receptor (EC 2.7.11.30)(Fragment) ACVRL1 503 H3BRM2 H3BRM2_HUMAN Integrin beta (Fragment) ITGB793 A9X9L0 A9X9L0_HUMAN Desmocollin 2 DSC2 901 B7Z6U6 B7Z6U6_HUMANIntegrin beta 471 B4DT61 B4DT61_HUMAN Syndecan 81 D2JYI4 D2JYI4_HUMANToll-like receptor 4 (Fragment) TLR4 124 E5RIG7 E5RIG7_HUMAN Integrinbeta (Fragment) ITGB2 120 E5RFI0 E5RFI0_HUMAN Integrin beta (Fragment)ITGB2 70 B7Z506 B7Z506_HUMAN Integrin beta 626 B4DTY9 B4DTY9_HUMANIntegrin beta 751 G3V2C6 G3V2C6_HUMAN Integrin alpha-7 (Fragment) ITGA7153 Q6PJ75 Q6PJ75_HUMAN Integrin beta (Fragment) ITGB2 758 B4DDX0B4DDX0_HUMAN cDNA FLJ59843, highly similar to Integrin alpha-X 264A9X9K9 A9X9K9_HUMAN Desmocollin 2 DSC2 901 H3BN02 H3BN02_HUMAN Integrinalpha-X ITGAX 1169 A0A024RAD5 A0A024RAD5_HUMANDolichyl-diphosphooligosaccharide--protein glycosyltransferase 48 kDasubunit DDOST 456 (Oligosaccharyl transferase 48 kDa subunit) (EC2.4.99.18) hCG_38871 A0A0C4DGS1 A0A0C4DGS1_HUMANDolichyl-diphosphooligosaccharide--protein glycosyltransferase 48 kDasubunit DDOST 439 (Oligosaccharyl transferase 48 kDa subunit) (EC2.4.99.18) B4DFP0 B4DFP0_HUMAN cDNA FLJ57804, highly similar toCadherin-9 382 Q53GF9 Q53GF9_HUMAN Full-length cDNA 5-PRIME end of cloneCS0DF013YM24 of Fetal brain of Homo sapiens 225 (Human) variant(Fragment) A8K2N5 A8K2N5_HUMAN Integrin beta 788 E7EUI6 E7EUI6_HUMANIntegrin beta (Fragment) ITGB1 152 Q4KMR2 Q4KMR2_HUMAN Delta-likeprotein JAG1 1218 Q59FA8 Q59FA8_HUMAN Integrin alpha-IIb variant(Fragment) 551 J3QQL2 J3QQL2_HUMAN Integrin beta (Fragment) ITGB4 114L7RXH0 L7RXH0_HUMAN Integrin, alpha V ITGAV 1048 A0A0A6YYA0A0A0A6YYA0_HUMAN Protein TMED7-TICAM2 TMED7-TICAM2 188 B4DL12B4DL12_HUMAN cDNA FLJ53754, highly similar to Transmembrane emp24domain-containing protein 10 177 B1AKT3 B1AKT3_HUMAN Transmembrane emp24domain-containing protein 5 TMED5 162 H7C5U2 H7C5U2_HUMAN Integrin beta(Fragment) ITGB5 401 F8W7F7 F8W7F7_HUMAN Transmembrane emp24domain-containing protein 4 TMED4 178 Q59H50 Q59H50_HUMAN Integrin beta(Fragment) 475 H3BUU9 H3BUU9_HUMAN Cadherin-11 CDH11 670 B4E0H8B4E0H8_HUMAN cDNA FLJ60385, highly similar to Integrin alpha-3 1037A8K6A5 A8K6A5_HUMAN cDNA FLJ77742, highly similar to Homo sapiensintegrin, alpha 5 (fibronectin receptor, 1049 alpha polypeptide), mRNAO60574 O60574_HUMAN Cadherin-7 (Fragment) CDH7 317 Q53HR4 Q53HR4_HUMANChromosome 15 open reading frame 22 variant (Fragment) 217 Q59H35Q59H35_HUMAN Protocadherin alpha 13 isoform 1 variant (Fragment) 921A0A024DAS2 A0A024DAS2_HUMAN Integrin beta (Fragment) ITGB2 80 A0A024RC42A0A024RC42_HUMAN Cadherin 2, type 1, N-cadherin (Neuronal), isoformCRA_b CDH2 hCG_22518 906 E7EMF1 E7EMF1_HUMAN Integrin alpha-2 ITGA2 815A0A024R9D1 A0A024R9D1_HUMAN Syndecan SDC2 hCG_15745 201 Q1PBM2Q1PBM2_HUMAN Integrin beta (Fragment) ITGB3 65 Q8NB64 Q8NB64_HUMAN cDNAFLJ34177 fis, clone FCBBF3016451, highly similar to RETINAL-CADHERIN 824Q59EB0 Q59EB0_HUMAN Kinase insert domain receptor (A type III receptortyrosine kinase) variant (Fragment) 1451 Q2YFE1 Q2YFE1_HUMAN Integrinbeta 443 Q3B7W7 Q3B7W7_HUMAN TMED7 protein (Fragment) TMED7 134 K7EQ63K7EQ63_HUMAN Transmembrane emp24 domain-containing protein 1 (Fragment)TMED1 191 A0A087WTR7 A0A087WTR7_HUMAN Cadherin-24 CDH24 314 K7EMU3K7EMU3_HUMAN Integrin alpha-3 (Fragment) ITGA3 117 Q49AG2 Q49AG2_HUMANTMED5 protein TMED5 172 A0A087WX36 A0A087WX36_HUMAN Integrin beta ITGB2378 Q9HAX1 Q9HAX1_HUMAN Desmocollin 3 (Fragment) DSC3 316 A0A087WXI5A0A087WXI5_HUMAN Cadherin-1 CDH1 903 M0R072 M0R072_HUMAN Transmembraneemp24 domain-containing protein 5 TMED5 120 Q8N9J3 Q8N9J3_HUMAN cDNAFLJ37047 fis, clone BRACE2012232, highly similar to Homo sapienscadherin 20 (CDH20) mRNA 335 Q8WWJ8 Q8WWJ8_HUMAN Integrin beta 378Q59H34 Q59H34_HUMAN Protocadherin alpha 4 isoform 1 variant (Fragment)921 A0A024DAE5 A0A024DAE5_HUMAN Integrin beta (Fragment) ITGB2 80 Q59H46Q59H46_HUMAN Integrin beta (Fragment) 1515 Q4VAI4 Q4VAI4_HUMAN CDH5protein CDH5 662 Q59FL1 Q59FL1_HUMAN Serine/threonine-protein kinasereceptor (EC 2.7.11.30) (Fragment) 514 Q2TAL1 Q2TAL1_HUMAN CDH24 proteinCDH24 314 Q59H74 Q59H74_HUMAN Integrin alpha 4 variant (Fragment) 854A0A087WX99 A0A087WX99_HUMAN Cadherin-4 CDH4 822 Q59FN1 Q59FN1_HUMANIntegrin beta (Fragment) 166 X6R3Y6 X6R3Y6_HUMAN Cadherin-8 CDH8 745Q59EQ1 Q59EQ1_HUMAN Cadherin 11, type 2 isoform 1 preproprotein variant(Fragment) 798 X5DQT8 X5DQT8_HUMAN Cadherin 10 type 2 isoform C(Fragment) CDH10 243 Q8N2D9 Q8N2D9_HUMAN cDNA PSEC0228 fis, cloneHEMBA1006099, weakly similar to COP-COATED VESICLE 146 MEMBRANE PROTEINP24 Q63HM4 Q63HM4_HUMAN Putative uncharacterized protein DKFZp686P18250DKFZp686P18250 758 A0A0E3XJU3 A0A0E3XJU3_HUMAN E-cadherin 1 CDH1 882Q68DY8 Q68DY8_HUMAN Putative uncharacterized protein DKFZp686I11137DKFZp686I11137 667

TABLE 2 Illustrative human Type II proteins which may be incorporatedinto the present compositions and methods include (as used herein“Entry” refers to the human Type II protein entry in the UniProtdatabase and “Entry name” refers to the human Type II protein entry inthe UniProt database): Entry Entry name Protein names Gene names LengthQ9BUJ0 ABHEA_HUMAN Protein ABHD14A (EC 3.—.—.—) (Alpha/beta hydrolasedomain-containing protein 14A) (Abhydrolase ABHD14A 271domain-containing protein 14A) UNQ1913/PRO4373 P08195 4F2_HUMAN 4F2cell-surface antigen heavy chain (4F2hc) (4F2 heavy chain antigen)(Lymphocyte SLC3A2 MDU1 630 activation antigen 4F2 large subunit)(Solute carrier family 3 member 2) (CD antigen CD98) Q9NPC4 A4GAT_HUMANLactosylceramide 4-alpha-galactosyltransferase (EC 2.4.1.228)(Alpha-1,4-N- A4GALT A14GALT A4GALT1 353 acetylglucosaminyltransferase)(Alpha-1,4-galactosyltransferase) (Alpha4Gal-T1) (CD77 synthase)(Globotriaosylceramide synthase) (Gb3 synthase) (P1/Pk synthase)(UDP-galactose: beta-D-galactosyl-beta1-R4-alpha-D-galactosyltransferase) Q9UNA3 A4GCT_HUMANAlpha-1,4-N-acetylglucosaminyltransferase (Alpha4GnT) (EC 2.4.1.—) A4GNT340 Q96SE0 ABHD1_HUMAN Protein ABHD1 (EC 3.1.1.—) (Alpha/beta hydrolasedomain-containing protein 1) ABHD1 LABH1 405 (Abhydrolasedomain-containing protein 1) (Lung alpha/beta hydrolase 1) P08910ABHD2_HUMAN Monoacylglycerol lipase ABHD2 (EC 3.1.1.23)(2-arachidonoylglycerol hydrolase) ABHD2 LABH2 425 (Abhydrolasedomain-containing protein 2) (Lung alpha/beta hydrolase 2) (ProteinPHPS1-2) Q9BV23 ABHD6_HUMAN Monoacylglycerol lipase ABHD6 (EC 3.1.1.23)(2-arachidonoylglycerol hydrolase) ABHD6 337 (Abhydrolasedomain-containing protein 6) Q7L211 ABHDD_HUMAN Protein ABHD13 (EC3.—.—.—) (Alpha/beta hydrolase domain-containing protein 13) ABHD13C13orf6 337 (Abhydrolase domain-containing protein 13) P22760 AAAD_HUMANArylacetamide deacetylase (EC 3.1.1.3) AADAC DAC 399 Q5VUY2 ADCL4_HUMANArylacetamide deacetylase-like 4 (EC 3.1.1.—) AADACL4 407 Q8WU67ABHD3_HUMAN Phospholipase ABHD3 (EC 3.1.1.32) (EC 3.1.1.4) (Abhydrolasedomain-containing protein 3) ABHD3 409 O00468 AGRIN_HUMAN Agrin [Cleavedinto: Agrin N-terminal 110 kDa subunit; Agrin C-terminal 110 kDasubunit; AGRN AGRIN 2067 Agrin C-terminal 90 kDa fragment (C90); AgrinC-terminal 22 kDa fragment (C22)] Q9Y673 ALG5_HUMAN Dolichyl-phosphatebeta-glucosyltransferase (DolP-glucosyltransferase) (EC 2.4.1.117) ALG5HSPC149 324 (Asparagine-linked glycosylation protein 5 homolog) P15144AMPN_HUMAN Aminopeptidase N (AP-N) (hAPN) (EC 3.4.11.2) (Alanylaminopeptidase) ANPEP APN CD13 PEPN 967 (Aminopeptidase M) (AP-M)(Microsomal aminopeptidase) (Myeloid plasma membrane glycoprotein CD13)(gp150) (CD antigen CD13) Q6Q4G3 AMPQ_HUMAN Aminopeptidase Q (AP-Q)(APQ) (EC 3.4.11.—) (CHL2 antigen) (Laeverin) LVRN AQPEP 990 Q16853AOC3_HUMAN Membrane primary amine oxidase (EC 1.4.3.21) (Copper amineoxidase) (HPAO) AOC3 VAP1 763 (Semicarbazide-sensitive amine oxidase)(SSAO) (Vascular adhesion protein 1) (VAP-1) Q9BT22 ALG1_HUMANChitobiosyldiphosphodolichol beta-mannosyltransferase (EC 2.4.1.142)(Asparagine- ALG1 HMAT1 HMT1 464 linked glycosylation protein 1 homolog)(Beta-1,4-mannosyltransferase) (GDP- PSEC0061 Man: GlcNAc2-PP-dolicholmannosyltransferase) (GDP-mannose-dolichol UNQ861/PRO1870diphosphochitobiose mannosyltransferase) (Mannosyltransferase-1) (MT-1)(hMat-1) Q07075 AMPE_HUMAN Glutamyl aminopeptidase (EAP) (EC 3.4.11.7)(Aminopeptidase A) (AP-A) (Differentiation ENPEP 957 antigen gp160) (CDantigen CD249) Q9HDC9 APMAP_HUMAN Adipocyte plasma membrane-associatedprotein (Protein BSCv) APMAP C20orf3 416 UNQ1869/PRO4305 P07306ASGR1_HUMAN Asialoglycoprotein receptor 1 (ASGP-R 1) (ASGPR 1) (C-typelectin domain family 4 ASGR1 CLEC4H1 291 member H1) (Hepatic lectin H1)(HL-1) Q9NR71 ASAH2_HUMAN Neutral ceramidase (N-CDase) (NCDase) (EC3.5.1.23) (Acylsphingosine deacylase 2) ASAH2 HNAC1 780 (BCDase)(LCDase) (hCD) (N-acylsphingosine amidohydrolase 2) (Non-lysosomalceramidase) [Cleaved into: Neutral ceramidase soluble form] Q5U4P2ASPH1_HUMAN Aspartate beta-hydroxylase domain-containing protein 1 (EC1.14.11.—) ASPHD1 390 Q9UN42 AT1B4_HUMAN Protein ATP1B4 (X,K-ATPasesubunit beta-m) (X/potassium-transporting ATPase subunit beta-m) ATP1B4357 Q99941 ATF6B_HUMAN Cyclic AMP-dependent transcription factor ATF-6beta (cAMP-dependent transcription ATF6B CREBL1 G13 703 factor ATF-6beta) (Activating transcription factor 6 beta) (ATF6-beta) (Protein G13)(cAMP response element-binding protein-related protein) (Creb-rp)(cAMP-responsive element-binding protein-like 1) [Cleaved into:Processed cyclic AMP-dependent transcription factor ATF-6 beta] Q6ICH7ASPH2_HUMAN Aspartate beta-hydroxylase domain-containing protein 2 (EC1.14.11.—) ASPHD2 369 P51164 ATP4B_HUMAN Potassium-transporting ATPasesubunit beta (Gastric H(+)/K(+) ATPase subunit beta) ATP4B 291 (Protonpump beta chain) Q12797 ASPH_HUMAN Aspartyl/asparaginyl beta-hydroxylase(EC 1.14.11.16) (Aspartate beta-hydroxylase) ASPH BAH 758 (ASPbeta-hydroxylase) (Peptide-aspartate beta-dioxygenase) P07307ASGR2_HUMAN Asialoglycoprotein receptor 2 (ASGP-R 2) (ASGPR 2) (C-typelectin domain family 4 member H2) ASGR2 CLEC4H2 311 (Hepatic lectin H2)(HL-2) P05026 AT1B1_HUMAN Sodium/potassium-transporting ATPase subunitbeta-1 (Sodium/potassium-dependent ATPase subunit beta-1) ATP1B1 ATP1B303 P14415 AT1B2_HUMAN Sodium/potassium-transporting ATPase subunitbeta-2 (Adhesion molecule in glia) ATP1B2 290 (AMOG)(Sodium/potassium-dependent ATPase subunit beta-2) P54709 AT1B3_HUMANSodium/potassium-transporting ATPase subunit beta-3(Sodium/potassium-dependent ATPase subunit ATP1B3 279 beta-3) (ATPB-3)(CD antigen CD298) P18850 ATF6A_HUMAN Cyclic AMP-dependent transcriptionfactor ATF-6 alpha (cAMP-dependent transcription ATF6 670 factor ATF-6alpha) (Activating transcription factor 6 alpha) (ATF6-alpha) [Cleavedinto: Processed cyclic AMP-dependent transcription factor ATF-6 alpha]Q9P2W7 B3GA1_HUMAN Galactosylgalactosylxylosylprotein3-beta-glucuronosyltransferase 1 (EC 2.4.1.135) B3GAT1 GLCATP 334(Beta-1,3-glucuronyltransferase 1) (Glucuronosyltransferase P) (GlcAT-P)(UDP- GlcUA: glycoprotein beta-1,3-glucuronyltransferase) (GlcUAT-P)Q9NPZ5 B3GA2_HUMAN Galactosylgalactosylxylosylprotein3-beta-glucuronosyltransferase 2 (EC 2.4.1.135) B3GAT2 GLCATS 323(Beta-1,3-glucuronyltransferase 2) (GlcAT-D)(UDP-glucuronosyltransferase S) (GlcAT-S) KIAA1963(Glucuronosyltransferase S) O94766 B3GA3_HUMANGalactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 3 (EC2.4.1.135) B3GAT3 335 (Beta-1,3-glucuronyltransferase 3)(Glucuronosyltransferase I) (GlcAT-I) (UDP-GlcUA: Gal beta-1,3-Gal-Rglucuronyltransferase) (GlcUAT-I) Q9Y2A9 B3GN3_HUMANN-acetyllactosaminide beta-1,3-N-acetylglucosaminyltransferase 3 (EC2.4.1.149) (Beta- B3GNT3 B3GALT8 3721,3-galactosyl-O-glycosyl-glycoproteinbeta-1,3-N-acetylglucosaminyltransferase) (EC TMEM3 2.4.1.146)(Beta-1,3-galactosyltransferase 8) (Beta-1,3-GalTase 8) (Beta3Gal-T8)UNQ637/PRO1266 (Beta3GalT8) (b3Gal-T8) (Beta-3-Gx-T8) (Core 1 extendingbeta-1,3-N- acetylglucosaminyltransferase) (Core1-beta3GlcNAcT)(Transmembrane protein 3) (UDP-Gal: beta-GlcNAcbeta-1,3-galactosyltransferase 8) (UDP-GlcNAc: betaGal beta-1,3-N-acetylglucosaminyltransferase 3) (BGnT-3) (Beta-1,3-Gn-T3)(Beta-1,3-N- acetylglucosaminyltransferase 3) (Beta3Gn-T3)(UDP-galactose: beta-N- acetylglucosamine beta-1,3-galactosyltransferase8) Q96L58 B3GT6_HUMAN Beta-1,3-galactosyltransferase 6 (Beta-1,3-GalTase6) (Beta3Gal-T6) (Beta3GalT6) (EC B3GALT6 329 2.4.1.134) (GAG GalTII)(Galactosyltransferase II) (Galactosylxylosylprotein 3-beta-galactosyltransferase) (UDP-Gal: betaGal beta 1,3-galactosyltransferasepolypeptide 6) O43505 B4GA1_HUMAN Beta-1,4-glucuronyltransferase 1 (EC2.4.1.—) (I-beta-1,3-N- B4GAT1 B3GNT1 415 acetylglucosaminyltransferase)(iGnT) (N-acetyllactosaminide beta-1,3-N- B3GNT6acetylglucosaminyltransferase) (Poly-N-acetyllactosamine extensionenzyme) (UDP- GlcNAc: betaGalbeta-1,3-N-acetylglucosaminyltransferase 1) O75752 B3GL1_HUMANUDP-GalNAc: beta-1,3-N-acetylgalactosaminyltransferase 1(Beta-1,3-GalNAc-T1) (EC B3GALNT1 331 2.4.1.79)(Beta-1,3-galactosyltransferase 3) (Beta-1,3-GalTase 3) (Beta3Gal-T3)B3GALT3 (Beta3GalT3) (b3Gal-T3) (Beta-3-Gx-T3)(Galactosylgalactosylglucosylceramide beta-D- UNQ531/PRO1074acetyl-galactosaminyltransferase) (Globoside synthase) (UDP-N-acetylgalactosamine: globotriaosylceramidebeta-1,3-N-acetylgalactosaminyltransferase) Q7Z7M8 B3GN8_HUMANUDP-GlcNAc: betaGal beta-1,3-N-acetylglucosaminyltransferase 8 (BGnT-8)(Beta-1,3- B3GNT8 B3GALT7 397 Gn-T8)(Beta-1,3-N-acetylglucosaminyltransferase 8) (Beta3Gn-T8) (EC 2.4.1.—)BGALT15 Q9Y2C3 B3GT5_HUMAN Beta-1,3-galactosyltransferase 5(Beta-1,3-GalTase 5) (Beta3Gal-T5) (Beta3GalT5) B3GALT5 310 (b3Gal-T5)(EC 2.4.1.—) (Beta-3-Gx-T5) (UDP-Gal: beta-GlcNAc beta-1,3-galactosyltransferase 5) (UDP-galactose: beta-N-acetylglucosaminebeta-1,3- galactosyltransferase 5) Q8NFL0 B3GN7_HUMAN UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 7 (BGnT-7) (Beta-1,3-B3GNT7 401 Gn-T7) (Beta-1,3-N-acetylglucosaminyltransferase 7)(Beta3Gn-T7) (EC 2.4.1.—) O43825 B3GT2_HUMANBeta-1,3-galactosyltransferase 2 (Beta-1,3-GalTase 2) (Beta3Gal-T2)(Beta3GalT2) (EC B3GALT2 422 2.4.1.—) (UDP-galactose:2-acetamido-2-deoxy-D-glucose 3beta-galactosyltransferase 2) Q00973B4GN1_HUMAN Beta-1,4 N-acetylgalactosaminyltransferase 1 (EC 2.4.1.92)((N-acetylneuraminyl)- B4GALNT1 GALGT 533 galactosylglucosylceramide)(GM2/GD2 synthase) (GalNAc-T) SIAT2 P15291 B4GT1_HUMANBeta-1,4-galactosyltransferase 1 (Beta-1,4-GalTase 1) (Beta4Gal-T1)(b4Gal-T1) (EC B4GALT1 GGTB2 398 2.4.1.—) (UDP-Gal: beta-GlcNAcbeta-1,4-galactosyltransferase 1) (UDP-galactose: beta-N-acetylglucosamine beta-1,4-galactosyltransferase 1) [Cleaved into:Processed beta-1,4- galactosyltransferase 1] [Includes: Lactose synthaseA protein (EC 2.4.1.22); N- acetyllactosamine synthase (EC 2.4.1.90)(Nal synthase); Beta-N- acetylglucosaminylglycopeptidebeta-1,4-galactosyltransferase (EC 2.4.1.38); Beta-N-acetylglucosaminyl-glycolipid beta-1,4-galactosyltransferase (EC2.4.1.—)] O60513 B4GT4_HUMAN Beta-1,4-galactosyltransferase 4(Beta-1,4-GalTase 4) (Beta4Gal-T4) (b4Gal-T4) (EC B4GALT4 344 2.4.1.—)(UDP-Gal: beta-GlcNAc beta-1,4-galactosyltransferase 4) (UDP-galactose:beta-N- UNQ552/PRO1109 acetylglucosamine beta-1,4-galactosyltransferase4) [Includes: N-acetyllactosamine synthase (EC 2.4.1.90) (Nal synthase);Lactotriaosylceramide beta-1,4- galactosyltransferase (EC 2.4.1.275)(Beta-N-acetylglucosaminyl-glycolipid beta-1,4- galactosyltransferase)]O43286 B4GT5_HUMAN Beta-1,4-galactosyltransferase 5 (Beta-1,4-GalTase 5)(Beta4Gal-T5) (b4Gal-T5) (EC B4GALT5 388 2.4.1.—) (Beta-1,4-GalT II)(UDP-Gal: beta-GlcNAc beta-1,4-galactosyltransferase 5) (UDP-galactose:beta-N-acetylglucosamine beta-1,4-galactosyltransferase 5) Q9NY97B3GN2_HUMAN N-acetyllactosaminidebeta-1,3-N-acetylglucosaminyltransferase 2 (EC 2.4.1.149) (Beta- B3GNT2B3GALT7 397 1,3-N-acetylglucosaminyltransferase 1) (BGnT-1)(Beta-1,3-Gn-T1) (Beta3Gn-T1) (Beta- B3GNT1 1,3-galactosyltransferase 7)(Beta-1,3-GalTase 7) (Beta3Gal-T7) (Beta3GalT7) (b3Gal- T7)(Beta-3-Gx-T7) (UDP-Gal: beta-GlcNAc beta-1,3-galactosyltransferase 7)(UDP- GlcNAc: betaGal beta-1,3-N-acetylglucosaminyltransferase 2)(BGnT-2) (Beta-1,3-Gn-T2) (Beta-1,3-N-acetylglucosaminyltransferase 2)(Beta3Gn-T2) (UDP-galactose: beta-N- acetylglucosaminebeta-1,3-galactosyltransferase 7) O60512 B4GT3_HUMANBeta-1,4-galactosyltransferase 3 (Beta-1,4-GalTase 3) (Beta4Gal-T3)(b4Gal-T3) (EC B4GALT3 393 2.4.1.—) (UDP-Gal: beta-GlcNAcbeta-1,4-galactosyltransferase 3) (UDP-galactose: beta-N-acetylglucosamine beta-1,4-galactosyltransferase 3) [Includes:N-acetyllactosamine synthase (EC 2.4.1.90) (Nal synthase);Beta-N-acetylglucosaminylglycopeptide beta-1,4- galactosyltransferase(EC 2.4.1.38); Beta-N-acetylglucosaminyl-glycolipid beta-1,4-galactosyltransferase (EC 2.4.1.—)] Q9Y5Z6 B3GT1_HUMANBeta-1,3-galactosyltransferase 1 (Beta-1,3-GalTase 1) (Beta3Gal-T1)(Beta3GalT1) (EC B3GALT1 326 2.4.1.—) (UDP-galactose:beta-N-acetyl-glucosamine-beta-1,3-galactosyltransferase 1) O96024B3GT4_HUMAN Beta-1,3-galactosyltransferase 4 (Beta-1,3-GalTase 4)(Beta3Gal-T4) (Beta3GalT4) B3GALT4 GALT4 378 (GalT4) (b3Gal-T4) (EC2.4.1.62) (Gal-T2) (Ganglioside galactosyltransferase) (UDP- galactose:beta-N-acetyl-galactosamine-beta-1,3-galactosyltransferase) Q76KP1B4GN4_HUMAN N-acetyl-beta-glucosaminyl-glycoprotein4-beta-N-acetylgalactosaminyltransferase 1 B4GALNT4 1039 (NGalNAc-T1)(EC 2.4.1.244) (Beta-1,4-N-acetylgalactosaminyltransferase IV)(Beta4GalNAc-T4) (Beta4GalNAcT4) O60909 B4GT2_HUMANBeta-1,4-galactosyltransferase 2 (Beta-1,4-GalTase 2) (Beta4Gal-T2)(b4Gal-T2) (EC B4GALT2 372 2.4.1.—) (UDP-Gal: beta-GlcNAcbeta-1,4-galactosyltransferase 2) (UDP-galactose: beta-N-acetylglucosamine beta-1,4-galactosyltransferase 2) [Includes: Lactosesynthase A protein (EC 2.4.1.22); N-acetyllactosamine synthase (EC2.4.1.90) (Nal synthase); Beta- N-acetylglucosaminylglycopeptidebeta-1,4-galactosyltransferase (EC 2.4.1.38); Beta-N-acetylglucosaminyl-glycolipid beta-1,4-galactosyltransferase (EC2.4.1.—)] Q9UBX8 B4GT6_HUMAN Beta-1,4-galactosyltransferase 6(Beta-1,4-GalTase 6) (Beta4Gal-T6) (b4Gal-T6) (UDP- B4GALT6 382 Gal:beta-GlcNAc beta-1,4-galactosyltransferase 6) (UDP-galactose: beta-N-acetylglucosamine beta-1,4-galactosyltransferase 6) [Includes:Glucosylceramide beta- 1,4-galactosyltransferase (EC 2.4.1.274)(Lactosylceramide synthase) (LacCer synthase) (UDP-Gal: glucosylceramidebeta-1,4-galactosyltransferase)] Q9UBV7 B4GT7_HUMANBeta-1,4-galactosyltransferase 7 (Beta-1,4-GalTase 7) (Beta4Gal-T7)(b4Gal-T7) (EC B4GALT7 XGALT1 327 2.4.1.—) (UDP-Gal: beta-GlcNAcbeta-1,4-galactosyltransferase 7) (UDP-galactose: beta-N- UNQ748/PRO1478acetylglucosamine beta-1,4-galactosyltransferase 7) [Includes:Xylosylprotein 4-beta- galactosyltransferase (EC 2.4.1.133)(Proteoglycan UDP-galactose: beta-xylose beta1,4- galactosyltransferaseI) (UDP-galactose: beta-xylose beta-1,4-galactosyltransferase) (XGPT)(XGalT-1) (Xylosylprotein beta-1,4-galactosyltransferase)] Q8NCR0B3GL2_HUMAN UDP-GalNAc: beta-1,3-N-acetylgalactosaminyltransferase 2(Beta-1,3-GalNAc-T2) (EC B3GALNT2 500 2.4.1.—)(Beta-1,3-N-acetylgalactosaminyltransferase II) Q9C0J1 B3GN4_HUMANN-acetyllactosaminide beta-1,3-N-acetylglucosaminyltransferase 4 (EC2.4.1.149) (UDP- B3GNT4 378 GlcNAc: betaGalbeta-1,3-N-acetylglucosaminyltransferase 4) (BGnT-4) (Beta-1,3-Gn-T4)UNQ1898/PRO4344 (Beta-1,3-N-acetylglucosaminyltransferase 4)(Beta3Gn-T4) Q6ZMB0 B3GN6_HUMANAcetylgalactosaminyl-O-glycosyl-glycoproteinbeta-1,3-N-acetylglucosaminyltransferase B3GNT6 384 (EC 2.4.1.147) (Core3 synthase) (UDP-GlcNAc: betaGal beta-1,3-N-acetylglucosaminyltransferase 6) (BGnT-6) (Beta-1,3-Gn-T6) (Beta-1,3-N-acetylglucosaminyltransferase 6) (Beta3Gn-T6) Q9BYG0 B3GN5_HUMANLactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase (EC2.4.1.206) B3GNT5 378 (Lactotriaosylceramide synthase) (Lc(3)Cersynthase) (Lc3 synthase) (UDP-GlcNAc: beta- Galbeta-1,3-N-acetylglucosaminyltransferase 5) (BGnT-5) (Beta-1,3-Gn-T5)(Beta-1,3-N- acetylglucosaminyltransferase 5) (Beta3Gn-T5) Q6UX72B3GN9_HUMAN UDP-GlcNAc: betaGal beta-1,3-N-acetylglucosaminyltransferase9 (BGnT-9) (Beta-1,3- B3GNT9 402 Gn-T9)(Beta-1,3-N-acetylglucosaminyltransferase 9) (Beta3Gn-T9) (EC 2.4.1.—)UNQ1922/PRO4397 Q6L9W6 B4GN3_HUMANBeta-1,4-N-acetylgalactosaminyltransferase 3 (B4GalNAcT3)(Beta4GalNAc-T3) B4GALNT3 998 (Beta4GalNAcT3) (EC 2.4.1.244)(Beta-1,4-N-acetylgalactosaminyltransferase III) (N-acetyl-beta-glucosaminyl-glycoprotein4-beta-N-acetylgalactosaminyltransferase 2) (NGalNAc-T2) Q6Y288B3GLT_HUMAN Beta-1,3-glucosyltransferase (Beta3Glc-T) (EC 2.4.1.—) (Beta3-glucosyltransferase) B3GLCT B3GALTL 498(Beta-3-glycosyltransferase-like) B3GTL Q8NHY0 B4GN2_HUMAN Beta-1,4N-acetylgalactosaminyltransferase 2 (EC 2.4.1.—) (Sd(a) beta-1,4-GalNAcB4GALNT2 GALGT2 566 transferase) (UDP-GalNAc: Neu5Aca2-3Galb-Rb1,4-N-acetylgalactosaminyltransferase) P0DN25 C1C1L_HUMANC1GALT1-specific chaperone 1-like protein C1GALT1C1L 315 P16442BGAT_HUMAN Histo-blood group ABO system transferase (Fucosylglycoprotein3-alpha- ABO 354 galactosyltransferase) (Fucosylglycoproteinalpha-N-acetylgalactosaminyltransferase)(Glycoprotein-fucosylgalactosidealpha-N-acetylgalactosaminyltransferase) (EC 2.4.1.40)(Glycoprotein-fucosylgalactoside alpha-galactosyltransferase) (EC2.4.1.37) (Histo-blood group A transferase) (A transferase) (Histo-bloodgroup B transferase) (B transferase) (NAGAT) [Cleaved into:Fucosylglycoprotein alpha-N-acetylgalactosaminyltransferase solubleform] Q9NS00 C1GLT_HUMAN Glycoprotein-N-acetylgalactosamine3-beta-galactosyltransferase 1 (EC 2.4.1.122) C1GALT1 363 (B3Gal-T8)(Core 1 O-glycan T-synthase) (Core 1 UDP-galactose: N-acetylgalactosamine-alpha-R beta 1,3-galactosyltransferase 1) (Beta-1,3-galactosyltransferase) (Core 1 beta1,3-galactosyltransferase 1)(C1GalT1) (Core 1 beta3-Gal-T1) Q10589 BST2_HUMAN Bone marrow stromalantigen 2 (BST-2) (HM1.24 antigen) (Tetherin) (CD antigen CD317) BST2180 Q96EU7 C1GLC_HUMAN C1GALT1-specific chaperone 1 (C38H2-likeprotein 1) (C38H2-L1) (Core 1 beta1,3- C1GALT1C1 318galactosyltransferase 2) (C1Gal-T2) (C1GalT2) (Core 1 beta3-Gal-T2)(Core 1 beta3- COSMC HSPC067 galactosyltransferase-specific molecularchaperone) MSTP143 UNQ273/PRO310 Q9UIR0 BTNL2_HUMAN Butyrophilin-likeprotein 2 (BTL-II) BTNL2 455 Q6P4E1 CASC4_HUMAN Protein CASC4 (Cancersusceptibility candidate gene 4 protein) CASC4 433 UNQ2573/PRO6308Q9NNX6 CD209_HUMAN CD209 antigen (C-type lectin domain family 4 memberL) (Dendritic cell-specific ICAM-3- CD209 CLEC4L 404 grabbingnon-integrin 1) (DC-SIGN) (DC-SIGN1) (CD antigen CD209) Q8WVQ1CANT1_HUMAN Soluble calcium-activated nucleotidase 1 (SCAN-1) (EC3.6.1.6) (Apyrase homolog) CANT1 SHAPY 401 (Putative MAPK-activatingprotein PM09) (Putative NF-kappa-B-activating protein 107) P29965CD40L_HUMAN CD40 ligand (CD40-L) (T-cell antigen Gp39) (TNF-relatedactivation protein) (TRAP) CD40LG CD40L 261 (Tumor necrosis factorligand superfamily member 5) (CD antigen CD154) [Cleaved into: TNFSF5TRAP CD40 ligand, membrane form; CD40 ligand, soluble form] P21854CD72_HUMAN B-cell differentiation antigen CD72 (Lyb-2) (CD antigen CD72)CD72 359 Q07108 CD69_HUMAN Early activation antigen CD69 (Activationinducer molecule) (AIM) (BL-AC/P26) (C-type CD69 CLEC2C 199 lectindomain family 2 member C) (EA1) (Early T-cell activation antigen p60)(GP32/28) (Leukocyte surface antigen Leu-23) (MLR-3) (CD antigen CD69)Q9ULG6 CCPG1_HUMAN Cell cycle progression protein 1 (Cell cycleprogression restoration protein 8) CCPG1 CCP8 757 CPR8 KIAA1254 Q8TDX6CGAT1_HUMAN Chondroitin sulfate N-acetylgalactosaminyltransferase 1(CsGalNAcT-1) (EC 2.4.1.174) CSGALNACT1 532 (Chondroitinbeta-1,4-N-acetylgalactosaminyltransferase 1) (Beta4GalNAcT-1) CHGNGALNACT1 UNQ656/PRO1287 P32970 CD70_HUMAN CD70 antigen (CD27 ligand)(CD27-L) (Tumor necrosis factor ligand superfamily member CD70 CD27L 1937) (CD antigen CD70) CD27LG TNFSF7 Q8IZ52 CHSS2_HUMAN Chondroitinsulfate synthase 2 (EC 2.4.1.175) (EC 2.4.1.226) (Chondroitin CHPF CSS2775 glucuronyltransferase 2) (Chondroitin-polymerizing factor) (ChPF)(Glucuronosyl-N- UNQ651/PRO1281 acetylgalactosaminyl-proteoglycan4-beta-N-acetylgalactosaminyltransferase II) (N-acetylgalactosaminyl-proteoglycan 3-beta-glucuronosyltransferase II) (N-acetylgalactosaminyltransferase 2) Q9GZX3 CHST6_HUMAN Carbohydratesulfotransferase 6 (EC 2.8.2.—) (Corneal N-acetylglucosamine-6-O- CHST6395 sulfotransferase) (C-GlcNAc6ST) (hCGn6ST)(Galactose/N-acetylglucosamine/N- acetylglucosamine 6-O-sulfotransferase4-beta) (GST4-beta) (N-acetylglucosamine 6-O- sulfotransferase 5)(GlcNAc6ST-5) (Gn6st-5) Q9NRB3 CHSTC_HUMAN Carbohydrate sulfotransferase12 (EC 2.8.2.5) (Chondroitin 4-O-sulfotransferase 2) CHST12 414(Chondroitin 4-sulfotransferase 2) (C4ST-2) (C4ST2) (SulfotransferaseHlo) UNQ500/PRO1017 P28907 CD38_HUMAN ADP-ribosyl cyclase/cyclicADP-ribose hydrolase 1 (EC 3.2.2.6) (2′-phospho-ADP-ribosyl CD38 300cyclase) (2′-phospho-ADP-ribosyl cyclase/2′-phospho-cyclic-ADP-ribosetransferase) (EC 2.4.99.20) (2′-phospho-cyclic-ADP-ribose transferase)(ADP-ribosyl cyclase 1) (ADPRC 1) (Cyclic ADP-ribose hydrolase 1) (cADPrhydrolase 1) (T10) (CD antigen CD38) Q8N6G5 CGAT2_HUMAN Chondroitinsulfate N-acetylgalactosaminyltransferase 2 (EC 2.4.1.174) (ChondroitinCSGALNACT2 542 beta-1,4-N-acetylgalactosaminyltransferase 2)(Beta4GalNAcT-2) (GalNAcT-2) CHGN2 GALNACT2 PRO0082 Q5QGZ9 CL12A_HUMANC-type lectin domain family 12 member A (C-type lectin-like molecule 1)(CLL-1) CLEC12A CLL1 265 (Dendritic cell-associated lectin 2) (DCAL-2)(Myeloid inhibitory C-type lectin-like DCAL2 MICL receptor) (MICL)Q9P2E5 CHPF2_HUMAN Chondroitin sulfate glucuronyltransferase (EC2.4.1.226) (CSGlcA-T) (Chondroitin CHPF2 CHSY3 772glucuronyltransferase) (Chondroitin polymerizing factor 2) (ChPF-2)(Chondroitin CSGLCAT synthase 3) (ChSy-3)(N-acetylgalactosaminyl-proteoglycan 3-beta- KIAA1402glucuronosyltransferase) UNQ299/PRO339 Q70JA7 CHSS3_HUMAN Chondroitinsulfate synthase 3 (EC 2.4.1.175) (EC 2.4.1.226) (Carbohydrate synthase2) CHSY3 CHSY2 CSS3 882 (Chondroitin glucuronyltransferase 3)(Chondroitin synthase 2) (ChSy-2) (Glucuronosyl-N-acetylgalactosaminyl-proteoglycan4-beta-N-acetylgalactosaminyltransferase II) (N-acetylgalactosaminyl-proteoglycan 3-beta-glucuronosyltransferase 3) (N-acetylgalactosaminyltransferase 3) Q9Y4C5 CHST2_HUMAN Carbohydratesulfotransferase 2 (EC 2.8.2.—) (Galactose/N-acetylglucosamine/N- CHST2GN6ST 530 acetylglucosamine 6-O-sulfotransferase 2) (GST-2)(N-acetylglucosamine 6-O- sulfotransferase 1) (GlcNAc6ST-1) (Gn6ST-1)Q8NCG5 CHST4_HUMAN Carbohydrate sulfotransferase 4 (EC 2.8.2.—)(Galactose/N-acetylglucosamine/N- CHST4 386 acetylglucosamine6-O-sulfotransferase 3) (GST-3) (High endothelial cells N-acetylglucosamine 6-O-sulfotransferase) (HEC-GlcNAc6ST) (L-selectinligand sulfotransferase) (LSST) (N-acetylglucosamine6-O-sulfotransferase 2) (GlcNAc6ST-2) (Gn6st-2) O43529 CHSTA_HUMANCarbohydrate sulfotransferase 10 (EC 2.8.2.—) (HNK-1 sulfotransferase)(HNK-1ST) (HNK1ST) (HuHNK-1ST) CHST10 356 Q92478 CLC2B_HUMAN C-typelectin domain family 2 member B (Activation-induced C-type lectin)(C-type lectin superfamily member 2) CLEC2B AICL 149(IFN-alpha-2b-inducing-related protein 1) CLECSF2 IFNRG1 Q6UXN8CLC9A_HUMAN C-type lectin domain family 9 member A CLEC9A 241UNQ9341/PRO34046 Q6UWU4 CF089_HUMAN Bombesin receptor-activated proteinC6orf89 (Amfion) C6orf89 BRAP 347 UNQ177/PRO203 Q86X52 CHSS1_HUMANChondroitin sulfate synthase 1 (EC 2.4.1.175) (EC 2.4.1.226)(Chondroitin CHSY1 CHSY CSS1 802 glucuronyltransferase 1) (Chondroitinsynthase 1) (ChSy-1) (Glucuronosyl-N- KIAA0990acetylgalactosaminyl-proteoglycan4-beta-N-acetylgalactosaminyltransferase 1) (N- UNQ756/PRO1487acetylgalactosaminyl-proteoglycan 3-beta-glucuronosyltransferase 1) (N-acetylgalactosaminyltransferase 1) Q8NET6 CHSTD_HUMAN Carbohydratesulfotransferase 13 (EC 2.8.2.5) (Chondroitin 4-O-sulfotransferase 3)CHST13 341 (Chondroitin 4-sulfotransferase 3) (C4ST-3) (C4ST3) Q7LFX5CHSTF_HUMAN Carbohydrate sulfotransferase 15 (EC 2.8.2.33) (B-cellRAG-associated gene protein) CHST15 BRAG 561 (hBRAG)(N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase) (GalNAc4S-6ST)GALNAC4S6ST KIAA0598 Q9P126 CLC1B_HUMAN C-type lectin domain family 1member B (C-type lectin-like receptor 2) (CLEC-2) CLEC1B CLEC2 229UNQ721/PRO1384 Q8IZS7 CLCL1_HUMAN C-type lectin-like domain family 1(Dendritic cell-associated lectin 1) (DC-associated CLECL1 DCAL1 167lectin-1) (DCAL-1) O43916 CHST1_HUMAN Carbohydrate sulfotransferase 1(EC 2.8.2.21) (Galactose/N-acetylglucosamine/N- CHST1 411acetylglucosamine 6-O-sulfotransferase 1) (GST-1) (Keratan sulfate Gal-6sulfotransferase) (KS6ST) (KSGal6ST) (KSST) Q7LGC8 CHST3_HUMANCarbohydrate sulfotransferase 3 (EC 2.8.2.17) (Chondroitin6-O-sulfotransferase 1) CHST3 479 (C6ST-1) (Chondroitin6-sulfotransferase) (Galactose/N-acetylglucosamine/N- acetylglucosamine6-O-sulfotransferase 0) (GST-0) Q9GZS9 CHST5_HUMAN Carbohydratesulfotransferase 5 (EC 2.8.2.—) (Galactose/N-acetylglucosamine/N- CHST5411 acetylglucosamine 6-O-sulfotransferase 4-alpha) (GST4-alpha)(Intestinal N- acetylglucosamine-6-O-sulfotransferase) (I-GlcNAc6ST)(Intestinal GlcNAc-6- sulfotransferase) (hIGn6ST) (N-acetylglucosamine6-O-sulfotransferase 3) (GlcNAc6ST- 3) (Gn6st-3) Q9NPF2 CHSTB_HUMANCarbohydrate sulfotransferase 11 (EC 2.8.2.5) (Chondroitin4-O-sulfotransferase 1) CHST11 352 (Chondroitin 4-sulfotransferase 1)(C4S-1) (C4ST-1) (C4ST1) Q9UMR7 CLC4A_HUMAN C-type lectin domain family4 member A (C-type lectin DDB27) (C-type lectin superfamily CLEC4ACLECSF6 237 member 6) (Dendritic cell immunoreceptor) (Lectin-likeimmunoreceptor) DCIR LLIR HDCGC13P Q8WXI8 CLC4D_HUMAN C-type lectindomain family 4 member D (C-type lectin superfamily member 8) (C-typeCLEC4D CLECSF8 MCL 215 lectin-like receptor 6) (CLEC-6) Q8N1N0CLC4F_HUMAN C-type lectin domain family 4 member F (C-type lectinsuperfamily member 13) (C-type CLEC4F CLECSF13 589 lectin 13) Q6UXB4CLC4G_HUMAN C-type lectin domain family 4 member G (Liver and lymph nodesinusoidal endothelial cell CLEC4G 293 C-type lectin) (LSECtin)UNQ431/PR0792 Q9BXN2 CLC7A_HUMAN C-type lectin domain family 7 member A(Beta-glucan receptor) (C-type lectin superfamily CLEC7A BGR 247 member12) (Dendritic cell-associated C-type lectin 1) (DC-associated C-typelectin 1) (Dectin-1) CLECSF12 DECTIN1 UNQ539/PRO1082 Q86VU5 CMTD1_HUMANCatechol O-methyltransferase domain-containing protein 1 (EC 2.1.1.—)COMTD1 262 UNQ766/PRO1558 Q9NS84 CHST7_HUMAN Carbohydratesulfotransferase 7 (EC 2.8.2.—) (EC 2.8.2.17) (Chondroitin 6- CHST7 486sulfotransferase 2) (C6ST-2)(Galactose/N-acetylglucosamine/N-acetylglucosamine 6-O- sulfotransferase5) (GST-5) (N-acetylglucosamine 6-O-sulfotransferase 4) (GlcNAc6ST-4)(Gn6st-4) Q8NCH0 CHSTE_HUMAN Carbohydrate sulfotransferase 14 (EC2.8.2.35) (Dermatan 4-sulfotransferase 1) (D4ST-1) (hD4ST1) CHST14 D4ST1376 UNQ1925/PRO4400 Q6UVW9 CLC2A_HUMAN C-type lectin domain family 2member A (Keratinocyte-associated C-type lectin) (KACL) CLEC2A KACL 174(Proliferation-induced lymphocyte-associated receptor) (PILAR)UNQ5792/PRO19597 Q8WTT0 CLC4C_HUMAN C-type lectin domain family 4 memberC (Blood dendritic cell antigen 2) (BDCA-2) (C-type CLEC4C BDCA2 213lectin superfamily member 7) (Dendritic lectin) (CD antigen CD303)CLECSF11 CLECSF7 DLEC HECL UNQ9361/PRO34150 Q9ULY5 CLC4E_HUMAN C-typelectin domain family 4 member E (C-type lectin superfamily member 9)CLEC4E CLECSF9 219 (Macrophage-inducible C-type lectin) MINCLEUNQ218/PRO244 Q9H2A9 CHST8_HUMAN Carbohydrate sulfotransferase 8 (EC2.8.2.—) (GalNAc-4-O-sulfotransferase 1) (GalNAc-4- CHST8 424 ST1)(GalNAc4ST-1) (N-acetylgalactosamine-4-O-sulfotransferase 1) Q8IUN9CLC10_HUMAN C-type lectin domain family 10 member A (C-type lectinsuperfamily member 14) CLEC10A 316 (Macrophage lectin 2) (CD antigenCD301) CLECSF13 CLECSF14 HML Q8NC01 CLC1A_HUMAN C-type lectin domainfamily 1 member A (C-type lectin-like receptor 1) (CLEC-1) CLEC1A CLEC1280 UNQ569/PRO1131 Q9UJ71 CLC4K_HUMAN C-type lectin domain family 4member K (Langerin) (CD antigen CD207) CD207 CLEC4K 328 Q7L1S5CHST9_HUMAN Carbohydrate sulfotransferase 9 (EC 2.8.2.—)(GalNAc-4-O-sulfotransferase 2) (GalNAc-4- CHST9 443 ST2) (GalNAc4ST-2)(N-acetylgalactosamine-4-O-sulfotransferase 2) UNQ2549/PRO6175 Q07065CKAP4_HUMAN Cytoskeleton-associated protein 4 (63-kDacytoskeleton-linking membrane protein) CKAP4 602 (Climp-63) (p63) Q2HXU8CL12B_HUMAN C-type lectin domain family 12 member B (Macrophage antigenH) CLEC12B 276 UNQ5782/PRO16089 Q6ZS10 CL17A_HUMAN C-type lectin domainfamily 17, member A (Prolectin) CLEC17A 378 Q9NY25 CLC5A_HUMAN C-typelectin domain family 5 member A (C-type lectin superfamily member 5)(Myeloid CLEC5A CLECSF5 188 DAP12-associating lectin 1) (MDL-1) MDL1Q6EIG7 CLC6A_HUMAN C-type lectin domain family 6 member A (C-type lectinsuperfamily member 10) (Dendritic CLEC6A CLECSF10 209 cell-associatedC-type lectin 2) (DC-associated C-type lectin 2) (Dectin-2) DECTIN2P21964 COMT_HUMAN Catechol O-methyltransferase (EC 2.1.1.6) COMT 271Q9UHP7 CLC2D_HUMAN C-type lectin domain family 2 member D (Lectin-likeNK cell receptor) (Lectin-like CLEC2D CLAX 191 transcript 1) (LLT-1)(Osteoclast inhibitory lectin) LLT1 OCIL Q9H2X3 CLC4M_HUMAN C-typelectin domain family 4 member M (CD209 antigen-like protein 1) (DC-SIGN-CLEC4M CD209L 399 related protein) (DC-SIGNR) (Dendritic cell-specificICAM-3-grabbing non-integrin 2) (DC- CD209L1 CD299 SIGN2) (Liver/lymphnode-specific ICAM-3-grabbing non-integrin) (L-SIGN) (CD antigen CD299)Q5KU26 COL12_HUMAN Collectin-12 (Collectin placenta protein 1) (CL-P1)(hCL-P1) (Nurse cell scavenger COLEC12 CLP1 742 receptor 2) (Scavengerreceptor class A member 4) (Scavenger receptor with C-type NSR2 SCARA4lectin) SRCL Q5TAT6 CODA1_HUMAN Collagen alpha-1(XIII) chain (COLXIIIA1)COL13A1 717 Q96BA8 CR3L1_HUMAN Cyclic AMP-responsive element-bindingprotein 3-like protein 1 (cAMP-responsive CREB3L1 OASIS 519element-binding protein 3-like protein 1) (Old astrocytespecifically-induced substance) PSEC0238 (OASIS) [Cleaved into:Processed cyclic AMP-responsive element-binding protein 3-like protein1] Q86Y22 CONA1_HUMAN Collagen alpha-1(XXIII) chain COL23A1 540 Q70SY1CR3L2_HUMAN Cyclic AMP-responsive element-binding protein 3-like protein2 (cAMP-responsive CREB3L2 BBF2H7 520 element-binding protein 3-likeprotein 2) (BBF2 human homolog on chromosome 7) [Cleaved into: Processedcyclic AMP-responsive element-binding protein 3-like protein 2] Q9UMD9COHA1_HUMAN Collagen alpha-1(XVII) chain (180 kDa bullous pemphigoidantigen 2) (Bullous COL17A1 BP180 1497 pemphigoid antigen 2) [Cleavedinto: 120 kDa linear IgA disease antigen (120 kDa linear BPAG2 IgAdermatosis antigen) (Linear IgA disease antigen 1) (LAD-1); 97 kDalinear IgA disease antigen (97 kDa linear IgA bullous dermatosisantigen) (97 kDa LAD antigen) (97-LAD) (Linear IgA bullous diseaseantigen of 97 kDa) (LABD97)] Q8N1L4 CP4Z2_HUMAN Putative inactivecytochrome P450 family member 4Z2 CYP4Z2P 340 Q9BXS0 COPA1_HUMANCollagen alpha-1(XXV) chain (Alzheimer disease amyloid-associatedprotein) (AMY) COL25A1 654 (CLAC-P) [Cleaved into: Collagen-likeAlzheimer amyloid plaque component (CLAC)] Q9Y5Q5 CORIN_HUMAN Atrialnatriuretic peptide-converting enzyme (EC 3.4.21.—) (Corin)(Heart-specific serine CORIN CRN 1042 proteinase ATC2)(Pro-ANP-converting enzyme) (Transmembrane protease serine 10) TMPRSS10[Cleaved into: Atrial natriuretic peptide-converting enzyme, N-terminalpropeptide; Atrial natriuretic peptide-converting enzyme, activatedprotease fragment; Atrial natriuretic peptide-converting enzyme, 180 kDasoluble fragment; Atrial natriuretic peptide- converting enzyme, 160 kDasoluble fragment; Atrial natriuretic peptide-converting enzyme, 100 kDasoluble fragment] Q86W10 CP4Z1_HUMAN Cytochrome P4504Z1 (EC 1.14.14.1)(CYPIVZ1) CYP4Z1 505 UNQ3060/PRO9882 O43889 CREB3_HUMAN CyclicAMP-responsive element-binding protein 3 (CREB-3) (cAMP-responsiveelement- CREB3 LZIP 395 binding protein 3) (Leucine zipper protein)(Luman) (Transcription factor LZIP-alpha) [Cleaved into: Processedcyclic AMP-responsive element-binding protein 3 (N-terminal Luman)(Transcriptionally active form)] Q8TEY5 CR3L4_HUMAN CyclicAMP-responsive element-binding protein 3-like protein 4 (cAMP-responsiveCREB3L4 AIBZIP 395 element-binding protein 3-like protein 4)(Androgen-induced basic leucine zipper protein) CREB4 JAL (AlbZIP)(Attaching to CRE-like 1) (ATCE1) (Cyclic AMP-responsive element-bindingprotein 4) (CREB-4) (cAMP-responsive element-binding protein 4)(Transcript induced in spermiogenesis protein 40) (Tisp40) (hJAL)[Cleaved into: Processed cyclic AMP- responsive element-binding protein3-like protein 4] Q68CJ9 CR3L3_HUMAN Cyclic AMP-responsiveelement-binding protein 3-like protein 3 (cAMP-responsive CREB3L3 CREBH461 element-binding protein 3-like protein 3) (Transcription factorCREB-H) [Cleaved into: HYST1481 Processed cyclic AMP-responsiveelement-binding protein 3-like protein 3] P37059 DHB2_HUMAN Estradiol17-beta-dehydrogenase 2 (EC 1.1.1.62) (17-beta-hydroxysteroid HSD17B2EDH17B2 387 dehydrogenase type 2) (17-beta-HSD 2) (20alpha-hydroxysteroid dehydrogenase) (20- SDR9C2 alpha-HSD) (E2DH)(Microsomal 17-beta-hydroxysteroid dehydrogenase) (Short chaindehydrogenase/reductase family 9C member 2) (Testosterone17-beta-dehydrogenase) (EC 1.1.1.239) P27487 DPP4_HUMAN Dipeptidylpeptidase 4 (EC 3.4.14.5) (ADABP) (Adenosine deaminase complexingprotein DPP4 ADCP2 CD26 766 2) (ADCP-2) (Dipeptidyl peptidase IV) (DPPIV) (T-cell activation antigen CD26) (TP103) (CD antigen CD26) [Cleavedinto: Dipeptidyl peptidase 4 membrane form (Dipeptidyl peptidase IVmembrane form); Dipeptidyl peptidase 4 soluble form (Dipeptidylpeptidase IV soluble form)] P28845 DHI1_HUMAN Corticosteroid11-beta-dehydrogenase isozyme 1 (EC 1.1.1.146) (11-beta-hydroxysteroidHSD11B1 HSD11 292 dehydrogenase 1) (11-DH) (11-beta-HSD1) (Short chaindehydrogenase/reductase family HSD11L SDR26C1 26C member 1) P09172DOPO_HUMAN Dopamine beta-hydroxylase (EC 1.14.17.1) (Dopaminebeta-monooxygenase) [Cleaved DBH 617 into: Soluble dopaminebeta-hydroxylase] Q8N608 DPP10_HUMAN Inactive dipeptidyl peptidase 10(Dipeptidyl peptidase IV-related protein 3) (DPRP-3) DPP10 DPRP3 796(Dipeptidyl peptidase X) (DPP X) (Dipeptidyl peptidase-like protein 2)(DPL2) KIAA1492 P42658 DPP6_HUMAN Dipeptidyl aminopeptidase-like protein6 (DPPX) (Dipeptidyl aminopeptidase-related DPP6 865 protein)(Dipeptidyl peptidase 6) (Dipeptidyl peptidase IV-like protein)(Dipeptidyl peptidase VI) (DPP VI) Q6IAN0 DRS7B_HUMANDehydrogenase/reductase SDR family member 7B (EC 1.1.—.—) (Short-chainDHRS7B SDR32C1 325 dehydrogenase/reductase family 32C member 1) CGI-93UNQ212/PRO238 O60344 ECE2_HUMAN Endothelin-converting enzyme 2 (ECE-2)[Includes: Methyltransferase-like region (EC ECE2 KIAA0604 883 2.1.1.—);Endothelin-converting enzyme 2 region (EC 3.4.24.71)] UNQ403/PRO740O75923 DYSF_HUMAN Dysferlin (Dystrophy-associated fer-1-like protein)(Fer-1-like protein 1) DYSF FER1L1 2080 O95672 ECEL1_HUMANEndothelin-converting enzyme-like 1 (EC 3.4.24.—) (Xce protein) ECEL1XCE 775 UNQ2431/PRO4991 Q92838 EDA_HUMAN Ectodysplasin-A (Ectodermaldysplasia protein) (EDA protein) [Cleaved into: EDA ED1 EDA2 391Ectodysplasin-A, membrane form; Ectodysplasin-A, secreted form] P42892ECE1_HUMAN Endothelin-converting enzyme 1 (ECE-1) (EC 3.4.24.71) ECE1770 Q92611 EDEM1_HUMAN ER degradation-enhancing alpha-mannosidase-likeprotein 1 EDEM1 EDEM 657 KIAA0212 O75354 ENTP6_HUMAN Ectonucleosidetriphosphate diphosphohydrolase 6 (NTPDase 6) (EC 3.6.1.6) (CD39 ENTPD6CD39L2 484 antigen-like 2) IL6ST2 P98073 ENTK_HUMAN Enteropeptidase (EC3.4.21.9) (Enterokinase) (Serine protease 7) (Transmembrane TMPRSS15ENTK 1019 protease serine 15) [Cleaved into: Enteropeptidasenon-catalytic heavy chain; PRSS7 Enteropeptidase catalytic light chain]P22413 ENPP1_HUMAN Ectonucleotide pyrophosphatase/phosphodiesterasefamily member 1 (E-NPP 1) ENPP1 M6S1 NPPS 925 (Membrane componentchromosome 6 surface marker 1) (Phosphodiesterase PC1 PDNP1 I/nucleotidepyrophosphatase 1) (Plasma-cell membrane glycoprotein PC-1) [Includes:Alkaline phosphodiesterase I (EC 3.1.4.1); Nucleotide pyrophosphatase(NPPase) (EC 3.6.1.9)] O14638 ENPP3_HUMAN Ectonucleotidepyrophosphatase/phosphodiesterase family member 3 (E-NPP 3) ENPP3 PDNP3875 (Phosphodiesterase I beta) (PD-Ibeta) (PhosphodiesteraseI/nucleotide pyrophosphatase 3) (CD antigen CD203c) [Includes: Alkalinephosphodiesterase I (EC 3.1.4.1); Nucleotide pyrophosphatase (NPPase)(EC 3.6.1.9)] O43909 EXTL3_HUMAN Exostosin-like 3 (EC 2.4.1.223)(EXT-related protein 1) (Glucuronyl-galactosyl- EXTL3 EXTL1L 919proteoglycan 4-alpha-N-acetylglucosaminyltransferase) (Hereditarymultiple exostoses EXTR1 KIAA0519 gene isolog) (Multiple exostosis-likeprotein 3) (Putative tumor suppressor protein EXTL3) Q6UWH4 F198B_HUMANProtein FAM198B (Expressed in nerve and epithelium during development)FAM198B C4orf18 519 ENED AD021 UNQ2512/PRO6001 Q9H0X4 F234A_HUMANProtein FAM234A (Protein ITFG3) FAM234A C16orf9 552 ITFG3 Q5VUD6FA69B_HUMAN Protein FAM69B FAM69B C9orf136 431 PP6977 Q8IUS5 EPHX4_HUMANEpoxide hydrolase 4 (EC 3.3.—.—) (Abhydrolase domain-containing protein7) (Epoxide EPHX4 ABHD7 362 hydrolase-related protein) EPHXRP O94905ERLN2_HUMAN Erlin-2 (Endoplasmic reticulum lipid raft-associated protein2) (Stomatin-prohibitin-flotillin- ERLIN2 C8orf2 339 HflC/Kdomain-containing protein 2) (SPFH domain-containing protein 2) SPFH2UNQ2441/PRO5003/ PRO9924 Q93063 EXT2_HUMAN Exostosin-2 (EC 2.4.1.224)(EC 2.4.1.225) (Glucuronosyl-N-acetylglucosaminyl- EXT2 718proteoglycan/N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase) (Multiple exostoses protein 2) (Putativetumor suppressor protein EXT2) Q9NZ08 ERAP1_HUMAN Endoplasmic reticulumaminopeptidase 1 (EC 3.4.11.—) (ARTS-1) (Adipocyte-derived ERAP1 APPILS941 leucine aminopeptidase) (A-LAP) (Aminopeptidase PILS)(Puromycin-insensitive leucyl- ARTS1 KIAA0525 specific aminopeptidase)(PILS-AP) (Type 1 tumor necrosis factor receptor shedding UNQ584/PRO1154aminopeptidase regulator) Q6P179 ERAP2_HUMAN Endoplasmic reticulumaminopeptidase 2 (EC 3.4.11.—) (Leukocyte-derived arginine ERAP2 LRAP960 aminopeptidase) (L-RAP) O75477 ERLN1_HUMAN Erlin-1 (Endoplasmicreticulum lipid raft-associated protein 1) (Protein KE04) (Stomatin-ERLIN1 C10orf69 346 prohibitin-flotillin-HflC/K domain-containingprotein 1) (SPFH domain-containing protein 1) KE04 KEO4 SPFH1 Q92935EXTL1_HUMAN Exostosin-like 1 (EC 2.4.1.224) (Exostosin-L)(Glucuronosyl-N-acetylglucosaminyl- EXTL1 EXTL 676 proteoglycan4-alpha-N-acetylglucosaminyltransferase) (Multiple exostosis-likeprotein) Q16394 EXT1_HUMAN Exostosin-1 (EC 2.4.1.224) (EC 2.4.1.225)(Glucuronosyl-N-acetylglucosaminyl- EXT1 746proteoglycan/N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase) (Multiple exostoses protein 1) (Putativetumor suppressor protein EXT1) Q9UBQ6 EXTL2_HUMAN Exostosin-like 2 (EC2.4.1.223) (Alpha-1,4-N-acetylhexosaminyltransferase EXTL2) EXTL2 EXTR2330 (Alpha-GalNAcT EXTL2) (EXT-related protein 2)(Glucuronyl-galactosyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase) [Cleaved into: Processedexostosin-like 2] Q0P6D2 FA69C_HUMAN Protein FAM69C FAM69C C18orf51 419Q5T7M9 FA69A_HUMAN Protein FAM69A FAM69A 428 Q9H9S5 FKRP_HUMANFukutin-related protein (EC 2.—.—.—) FKRP 495 Q8N539 FBCD1_HUMANFibrinogen C domain-containing protein 1 FIBCD1 461 UNQ701/PRO1346P06734 FCER2_HUMAN Low affinity immunoglobulin epsilon Fc receptor(BLAST-2) (C-type lectin domain family 4 FCER2 CD23A 321 member J)(Fc-epsilon-RII) (Immunoglobulin E-binding factor) (Lymphocyte IgEreceptor) CLEC4J FCE2 (CD antigen CD23) [Cleaved into: Low affinityimmunoglobulin epsilon Fc receptor IGEBF membrane-bound form; Lowaffinity immunoglobulin epsilon Fc receptor soluble form] O75072FKTN_HUMAN Fukutin (EC 2.—.—.—) (Fukuyama-type congenital musculardystrophy protein) FKTN FCMD 461 Q04609 FOLH1_HUMAN Glutamatecarboxypeptidase 2 (EC 3.4.17.21) (Cell growth-inhibiting gene 27protein) FOLH1 FOLH 750 (Folate hydrolase 1) (Folylpoly-gamma-glutamatecarboxypeptidase) (FGCP) (Glutamate NAALAD1 PSM carboxypeptidase II)(GCPII) (Membrane glutamate carboxypeptidase) (mGCP) (N- PSMA GIG27acetylated-alpha-linked acidic dipeptidase I) (NAALADase I)(Prostate-specific membrane antigen) (PSM) (PSMA)(Pteroylpoly-gamma-glutamate carboxypeptidase) Q9BYC5 FUT8_HUMANAlpha-(1,6)-fucosyltransferase (Alpha1-6FucT) (EC 2.4.1.68)(Fucosyltransferase 8) FUT8 575 (GDP-L-Fuc:N-acetyl-beta-D-glucosaminide alpha1,6-fucosyltransferase) (GDP-fucose--glycoprotein fucosyltransferase) (Glycoprotein6-alpha-L-fucosyltransferase) P19526 FUT1_HUMAN Galactoside2-alpha-L-fucosyltransferase 1 (EC 2.4.1.69) (Alpha(1,2)FT 1) (Bloodgroup FUT1 H HSC 365 H alpha 2-fucosyltransferase)(Fucosyltransferase 1) (GDP-L-fucose: beta-D-galactoside2-alpha-L-fucosyltransferase 1) P51993 FUT6_HUMANAlpha-(1,3)-fucosyltransferase 6 (EC 2.4.1.65) (Fucosyltransferase 6)FUT6 FCT3A 359 (Fucosyltransferase VI) (Fuc-TVI) (FucT-VI) (Galactoside3-L-fucosyltransferase) Q9H3Q3 G3ST2_HUMANGalactose-3-O-sulfotransferase 2 (Gal3ST-2) (EC 2.8.2.—)(Beta-galactose-3-O- GAL3ST2 GP3ST 398 sulfotransferase 2)(Gal-beta-1,3-GalNAc 3′-sulfotransferase 2) (Glycoprotein beta-Gal3′-sulfotransferase 2) Q10981 FUT2_HUMAN Galactoside2-alpha-L-fucosyltransferase 2 (EC 2.4.1.69) (Alpha(1,2)FT 2) FUT2 SEC2343 (Fucosyltransferase 2) (GDP-L-fucose: beta-D-galactoside2-alpha-L-fucosyltransferase 2) (SE2) (Secretor blood groupalpha-2-fucosyltransferase) (Secretor factor) (Se) P22083 FUT4_HUMANAlpha-(1,3)-fucosyltransferase 4 (EC 2.4.1.—) (ELAM-1 ligandfucosyltransferase) FUT4 ELFT FCT3A 530 (Fucosyltransferase 4)(Fucosyltransferase IV) (Fuc-TIV) (FucT-IV) (Galactoside 3-L-fucosyltransferase) Q96A11 G3ST3_HUMAN Galactose-3-O-sulfotransferase 3(Gal3ST-3) (EC 2.8.2.—) (Beta-galactose-3-O- GAL3ST3 431sulfotransferase 3) (Gal3ST3) (Gal-beta-1,3-GalNAc 3′-sulfotransferase3) Q10472 GALT1_HUMAN Polypeptide N-acetylgalactosaminyltransferase 1(EC 2.4.1.41) (Polypeptide GalNAc GALNT1 559 transferase 1) (GalNAc-T1)(pp-GaNTase 1) (Protein-UDP acetylgalactosaminyltransferase 1)(UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase 1) [Cleavedinto: Polypeptide N- acetylgalactosaminyltransferase 1 soluble form]Q10471 GALT2_HUMAN Polypeptide N-acetylgalactosaminyltransferase 2 (EC2.4.1.41) (Polypeptide GalNAc GALNT2 571 transferase 2) (GalNAc-T2)(pp-GaNTase 2) (Protein-UDP acetylgalactosaminyltransferase 2)(UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase 2) [Cleavedinto: Polypeptide N- acetylgalactosaminyltransferase 2 soluble form]Q14435 GALT3_HUMAN Polypeptide N-acetylgalactosaminyltransferase 3 (EC2.4.1.41) (Polypeptide GalNAc GALNT3 633 transferase 3) (GalNAc-T3)(pp-GaNTase 3) (Protein-UDP acetylgalactosaminyltransferase 3)(UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase 3) Q8NCL4GALT6_HUMAN Polypeptide N-acetylgalactosaminyltransferase 6 (EC2.4.1.41) (Polypeptide GalNAc GALNT6 622 transferase 6) (GalNAc-T6)(pp-GaNTase 6) (Protein-UDP acetylgalactosaminyltransferase 6)(UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase 6) Q6P4F1FUT10_HUMAN Alpha-(1,3)-fucosyltransferase 10 (EC 2.4.1.—)(Fucosyltransferase X) (Fuc-TX) (FucT-X) FUT10 479 (Galactoside3-L-fucosyltransferase 10) (Fucosyltransferase 10) Q99999 G3ST1_HUMANGalactosylceramide sulfotransferase (GalCer sulfotransferase) (EC2.8.2.11) (3′- GAL3ST1 CST 423 phosphoadenosine-5′-phosphosulfate:GalCer sulfotransferase) (3′- phosphoadenylylsulfate: galactosylceramide3′-sulfotransferase) (Cerebroside sulfotransferase) Q96RP7 G3ST4_HUMANGalactose-3-O-sulfotransferase 4 (Gal3ST-4) (EC 2.8.2.—)(Beta-galactose-3-O- GAL3ST4 PP6968 486 sulfotransferase 4)(Gal-beta-1,3-GalNAc 3′-sulfotransferase) Q9NY28 GALT8_HUMAN Probablepolypeptide N-acetylgalactosaminyltransferase 8 (EC 2.4.1.41)(Polypeptide GALNT8 637 GalNAc transferase 8) (GalNAc-T8) (pp-GaNTase 8)(Protein-UDP acetylgalactosaminyltransferase 8) (UDP-GalNAc: polypeptideN- acetylgalactosaminyltransferase 8) Q9HCQ5 GALT9_HUMAN PolypeptideN-acetylgalactosaminyltransferase 9 (EC 2.4.1.41) (Polypeptide GalNAcGALNT9 603 transferase 9) (GalNAc-T9) (pp-GaNTase 9) (Protein-UDPacetylgalactosaminyltransferase 9) (UDP-GalNAc: polypeptide N-acetylgalactosaminyltransferase 9) Q495W5 FUT11_HUMANAlpha-(1,3)-fucosyltransferase 11 (EC 2.4.1.—) (Fucosyltransferase XI)(Fuc-TXI) (FucT- FUT11 492 XI) (Galactoside 3-L-fucosyltransferase 11)(Fucosyltransferase 11) P21217 FUT3_HUMAN Galactoside3(4)-L-fucosyltransferase (EC 2.4.1.65) (Blood group Lewis alpha-4- FUT3FT3B LE 361 fucosyltransferase) (Lewis FT) (Fucosyltransferase 3)(Fucosyltransferase III) (FucT-III) Q9Y231 FUT9_HUMANAlpha-(1,3)-fucosyltransferase 9 (EC 2.4.1.—) (Fucosyltransferase 9)(Fucosyltransferase FUT9 359 IX) (Fuc-TIX) (FucT-IX) (Galactoside3-L-fucosyltransferase) Q7Z7M9 GALT5_HUMAN PolypeptideN-acetylgalactosaminyltransferase 5 (EC 2.4.1.41) (Polypeptide GalNAcGALNT5 940 transferase 5) (GalNAc-T5) (pp-GaNTase 5) (Protein-UDPacetylgalactosaminyltransferase 5) (UDP-GalNAc: polypeptide N-acetylgalactosaminyltransferase 5) Q9P109 GCNT4_HUMANBeta-1,3-galactosyl-O-glycosyl-glycoproteinbeta-1,6-N-acetylglucosaminyltransferase 4 GCNT4 453 (EC 2.4.1.102)(Core 2-branching enzyme 3) (Core2-GlcNAc-transferase 3) (C2GnT3) Q6ZNI0GCNT7_HUMAN Beta-1,3-galactosyl-O-glycosyl-glycoproteinbeta-1,6-N-acetylglucosaminyltransferase 7 GCNT7 C20orf105 430 (EC2.4.1.—) Q11128 FUT5_HUMAN Alpha-(1,3)-fucosyltransferase 5 (EC2.4.1.65) (Fucosyltransferase 5) FUT5 374 (Fucosyltransferase V)(Fuc-TV) (FucT-V) (Galactoside 3-L-fucosyltransferase) Q11130 FUT7_HUMANAlpha-(1,3)-fucosyltransferase 7 (EC 2.4.1.—) (Fucosyltransferase 7)(Fucosyltransferase FUT7 342 VII) (Fuc-TVII) (FucT-VII) (Galactoside3-L-fucosyltransferase) (Selectin ligand synthase) Q02742 GCNT1_HUMANBeta-1,3-galactosyl-O-glycosyl-glycoproteinbeta-1,6-N-acetylglucosaminyltransferase GCNT1 NACGT2 428 (EC 2.4.1.102)(Core 2-branching enzyme) (Core2-GlcNAc-transferase) (C2GNT) (Core 2GNT) Q8N5D6 GBGT1_HUMAN Globosidealpha-1,3-N-acetylgalactosaminyltransferase 1 (EC 2.4.1.—) (ForssmanGBGT1 347 glycolipid synthase-like protein) UNQ2513/PRO6002 Q5T4J0GCNT6_HUMAN Beta-1,3-galactosyl-O-glycosyl-glycoproteinbeta-1,6-N-acetylglucosaminyltransferase 6 (EC 2.4.1.—) GCNT6 391 Q4G0N0GGTA1_HUMAN Inactive N-acetyllactosaminidealpha-1,3-galactosyltransferase (Glycoprotein alpha- GGTA1P GGTA1 100galactosyltransferase 1 pseudogene) Q68CQ7 GL8D1_HUMANGlycosyltransferase 8 domain-containing protein 1 (EC 2.4.1.—) GLT8D1GALA4A 371 AD-017 MSTP137 UNQ572/PRO1134 Q8N4A0 GALT4_HUMAN PolypeptideN-acetylgalactosaminyltransferase 4 (EC 2.4.1.41) (Polypeptide GalNAcGALNT4 578 transferase 4) (GalNAc-T4) (pp-GaNTase 4) (Protein-UDPacetylgalactosaminyltransferase 4) (UDP-GalNAc: polypeptide N-acetylgalactosaminyltransferase 4) Q86SF2 GALT7_HUMANN-acetylgalactosaminyltransferase 7 (EC 2.4.1.—) (Polypeptide GalNActransferase 7) GALNT7 657 (GalNAc-T7) (pp-GaNTase 7) (Protein-UDPacetylgalactosaminyltransferase 7) (UDP- GalNAc: polypeptideN-acetylgalactosaminyltransferase 7) O95395 GCNT3_HUMANBeta-1,3-galactosyl-O-glycosyl-glycoproteinbeta-1,6-N-acetylglucosaminyltransferase 3 GCNT3 438 (EC 2.4.1.102) (EC2.4.1.150) (C2GnT-mucin type) (C2GnT-M) (hC2GnT-M) (Core 2/core 4beta-1,6-N-acetylglucosaminyltransferase) (C2/4GnT) P19440 GGT1_HUMANGamma-glutamyltranspeptidase 1 (GGT 1) (EC 2.3.2.2)(Gamma-glutamyltransferase 1) GGT1 GGT 569 (Glutathione hydrolase 1) (EC3.4.19.13) (Leukotriene-C4 hydrolase) (EC 3.4.19.14) (CD antigen CD224)[Cleaved into: Gamma-glutamyltranspeptidase 1 heavy chain; Gamma-glutamyltranspeptidase 1 light chain] Q7Z4J2 GL6D1_HUMANGlycosyltransferase 6 domain-containing protein 1 (EC 2.4.1.—)(Galactosyltransferase GLT6D1 GLTDC1 308 family 6 domain-containing 1)GT6M7 O94923 GLCE_HUMAN D-glucuronyl C5-epimerase (EC 5.1.3.17) (Heparansulfate C5-epimerase) (Hsepi) GLCE KIAA0836 617 (Heparin/heparansulfate: glucuronic acid C5-epimerase) (Heparosan-N-sulfate- glucuronate5-epimerase) Q86SR1 GLT10_HUMAN PolypeptideN-acetylgalactosaminyltransferase 10 (EC 2.4.1.41) (Polypeptide GalNAcGALNT10 603 transferase 10) (GalNAc-T10) (pp-GaNTase 10) (Protein-UDPacetylgalactosaminyltransferase 10) (UDP-GalNAc: polypeptide N-acetylgalactosaminyltransferase 10) Q8IXK2 GLT12_HUMAN PolypeptideN-acetylgalactosaminyltransferase 12 (EC 2.4.1.41) (Polypeptide GalNAcGALNT12 581 transferase 12) (GalNAc-T12) (pp-GaNTase 12) (Protein-UDPacetylgalactosaminyltransferase 12) (UDP-GalNAc: polypeptide N-acetylgalactosaminyltransferase 12) Q96FL9 GLT14_HUMAN PolypeptideN-acetylgalactosaminyltransferase 14 (EC 2.4.1.41) (Polypeptide GalNAcGALNT14 552 transferase 14) (GalNAc-T14) (pp-GaNTase 14) (Protein-UDPUNQ2434/PRO4994 acetylgalactosaminyltransferase 14) (UDP-GalNAc:polypeptide N- acetylgalactosaminyltransferase 14) Q8N428 GLT16_HUMANPolypeptide N-acetylgalactosaminyltransferase 16 (EC 2.4.1.41)(Polypeptide GalNAc GALNT16 GALNTL1 558 transferase 16) (GalNAc-T16)(Polypeptide GalNAc transferase-like protein 1) (GalNAc-T- KIAA1130 likeprotein 1) (pp-GaNTase-like protein 1) (Polypeptide N-acetylgalactosaminyltransferase-like protein 1) (Protein-UDPacetylgalactosaminyltransferase-like protein 1) (UDP-GalNAc: polypeptideN- acetylgalactosaminyltransferase-like protein 1) P36269 GGT5_HUMANGamma-glutamyltransferase 5 (GGT 5) (EC 2.3.2.2) (Gamma-glutamyltranspeptidase- GGT5 GGTLA1 586 related enzyme) (GGT-rel)(Gamma-glutamyltransferase-like activity 1) (Gamma-glutamyltranspeptidase 5) (Glutathione hydrolase 5) (EC 3.4.19.13)(Leukotriene-C4 hydrolase) (EC 3.4.19.14) [Cleaved into:Gamma-glutamyltransferase 5 heavy chain; Gamma-glutamyltransferase 5light chain] Q6P531 GGT6_HUMAN Gamma-glutamyltransferase 6 (GGT 6) (EC2.3.2.2) (Gamma-glutamyltranspeptidase 6) GGT6 493 (Glutathionehydrolase 6) (EC 3.4.19.13) [Cleaved into: Gamma-glutamyltransferase 6heavy chain; Gamma-glutamyltransferase 6 light chain] Q9UJ14 GGT7_HUMANGamma-glutamyltransferase 7 (GGT 7) (EC 2.3.2.2)(Gamma-glutamyltransferase-like 3) GGT7 GGTL3 662(Gamma-glutamyltransferase-like 5) (Gamma-glutamyltranspeptidase 7)(Glutathione GGTL5 hydrolase 7) (EC 3.4.19.13) [Cleaved into:Gamma-glutamyltransferase 7 heavy chain; Gamma-glutamyltransferase 7light chain] Q6ZMI3 GLDN_HUMAN Gliomedin [Cleaved into: Gliomedinshedded ectodomain] GLDN COLM 551 UNQ9339/PRO34011 Q8IUC8 GLT13_HUMANPolypeptide N-acetylgalactosaminyltransferase 13 (EC 2.4.1.41)(Polypeptide GalNAc GALNT13 KIAA1918 556 transferase 13) (GalNAc-T13)(pp-GaNTase 13) (Protein-UDP acetylgalactosaminyltransferase 13)(UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase 13) Q6P9A2GLT18_HUMAN Polypeptide N-acetylgalactosaminyltransferase 18 (EC2.4.1.41) (Polypeptide GalNAc GALNT18 GALNTL4 607 transferase 18)(GalNAc-T18) (Polypeptide GalNAc transferase-like protein 4) (GalNAc-T-like protein 4) (pp-GaNTase-like protein 4) (Polypeptide N-acetylgalactosaminyltransferase-like protein 4) (Protein-UDPacetylgalactosaminyltransferase-like protein 4) (UDP-GalNAc: polypeptideN- acetylgalactosaminyltransferase-like protein 4) Q49A17 GLTL6_HUMANPolypeptide N-acetylgalactosaminyltransferase-like 6 (EC 2.4.1.41)(Polypeptide GalNAc GALNTL6 GALNT17 601 transferase 17) (GalNAc-T17)(pp-GaNTase 17) (Protein-UDP acetylgalactosaminyltransferase 17)(Putative polypeptide N- acetylgalactosaminyltransferase 17)(UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase 17) Q3T906GNPTA_HUMAN N-acetylglucosamine-1-phosphotransferase subunits alpha/beta(EC 2.7.8.17) (GlcNAc- GNPTAB GNPTA 1256 1-phosphotransferase subunitsalpha/beta) (Stealth protein GNPTAB) (UDP-N- KIAA1208acetylglucosamine-1-phosphotransferase subunits alpha/beta) [Cleavedinto: N- acetylglucosamine-1-phosphotransferase subunit alpha;N-acetylglucosamine-1- phosphotransferase subunit beta] A6NGU5GGT3_HUMAN Putative gamma-glutamyltranspeptidase 3 (GGT 3) (EC 2.3.2.2)(Gamma- GGT3P GGT3 568 glutamyltransferase 3) (Glutathione hydrolase 3)(EC 3.4.19.13) [Cleaved into: Putative gamma-glutamyltranspeptidase 3heavy chain; Putative gamma-glutamyltranspeptidase 3 light chain] Q9H1C3GL8D2_HUMAN Glycosyltransferase 8 domain-containing protein 2 (EC2.4.1.—) GLT8D2 GALA4A 349 UNQ1901/PRO4347 Q8N3T1 GLT15_HUMANPolypeptide N-acetylgalactosaminyltransferase 15 (EC 2.4.1.41)(Polypeptide GalNAc GALNT15 GALNTL2 639 transferase-like protein 2)(GalNAc-T-like protein 2) (pp-GaNTase-like protein 2) UNQ770/PRO1564(Polypeptide N-acetylgalactosaminyltransferase-like protein 2)(Protein-UDP acetylgalactosaminyltransferase-like protein 2)(UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase-like protein2) Q6IS24 GLTL3_HUMAN Putative polypeptideN-acetylgalactosaminyltransferase-like protein 3 (EC 2.4.1.41) WBSCR17598 (Polypeptide GalNAc transferase-like protein 3) (GalNAc-T-likeprotein 3) (pp-GaNTase- GALNTL3 like protein 3) (Protein-UDPacetylgalactosaminyltransferase-like protein 3) (UDP- GalNAc:polypeptide N-acetylgalactosaminyltransferase-like protein 3)(Williams-Beuren syndrome chromosomal region 17 protein) Q8NCW6GLT11_HUMAN Polypeptide N-acetylgalactosaminyltransferase 11 (EC2.4.1.41) (Polypeptide GalNAc GALNT11 608 transferase 11) (GalNAc-T11)(pp-GaNTase 11) (Protein-UDP acetylgalactosaminyltransferase 11)(UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase 11) Q7Z4T8GLTL5_HUMAN Inactive polypeptide N-acetylgalactosaminyltransferase-likeprotein 5 (Polypeptide GALNTL5 GALNT15 443 GalNAc transferase 15)(GalNAc-T15) (pp-GaNTase 15) (Protein-UDPacetylgalactosaminyltransferase 15) (UDP-GalNAc: polypeptide N-acetylgalactosaminyltransferase 15) Q8N0V5 GNT2A_HUMANN-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase (N-GCNT2 GCNT5 II 402 acetylglucosaminyltransferase) (EC 2.4.1.150)(I-branching enzyme) (IGNT) NACGT1 O00461 GOLI4_HUMAN Golgi integralmembrane protein 4 (Golgi integral membrane protein, cis) (GIMPc) (GolgiGOLIM4 GIMPC 696 phosphoprotein 4) (Golgi-localized phosphoprotein of130 kDa) (Golgi phosphoprotein of 130 kDa) GOLPH4 GPP130 Q8NBJ4GOLM1_HUMAN Golgi membrane protein 1 (Golgi membrane protein GP73)(Golgi phosphoprotein 2) GOLM1 C9orf155 401 GOLPH2 PSEC0242UNQ686/PRO1326 A0PJZ3 GXLT2_HUMAN Glucoside xylosyltransferase 2 (EC2.4.2.n2) (Glycosyltransferase 8 domain-containing protein 4) GXYLT2GLT8D4 443 Q4G148 GXLT1_HUMAN Glucoside xylosyltransferase 1 (EC2.4.2.n2) (Glycosyltransferase 8 domain-containing protein 3) GXYLT1GLT8D3 440 Q96MM7 H6ST2_HUMAN Heparan-sulfate 6-O-sulfotransferase 2(HS6ST-2) (EC 2.8.2.—) HS6ST2 PSEC0092 605 O60243 H6ST1_HUMANHeparan-sulfate 6-O-sulfotransferase 1 (HS6ST-1) (EC 2.8.2.—) HS6ST1HS6ST 411 Q8IZP7 H6ST3_HUMAN Heparan-sulfate 6-O-sulfotransferase 3(HS6ST-3) (EC 2.8.2.—) HS6ST3 471 P04233 HG2A_HUMAN HLA class IIhistocompatibility antigen gamma chain (HLA-DR antigens-associated CD74DHLAG 296 invariant chain) (Ia antigen-associated invariant chain) (Ii)(p33) (CD antigen CD74) Q7LGA3 HS2ST_HUMAN Heparan sulfate2-O-sulfotransferase 1 (2-O-sulfotransferase) (2OST) (EC 2.8.2.—) HS2ST1HS2ST 356 KIAA0448 Q8IZT8 HS3S5_HUMAN Heparan sulfate glucosamine3-O-sulfotransferase 5 (EC 2.8.2.23) (Heparan sulfate D- HS3ST5 3OST5346 glucosaminyl 3-O-sulfotransferase 5) (3-OST-5) (Heparan sulfate3-O-sulfotransferase 5) (h3-OST-5) HS3OST5 P05981 HEPS_HUMAN Serineprotease hepsin (EC 3.4.21.106) (Transmembrane protease serine 1)[Cleaved HPN TMPRSS1 417 into: Serine protease hepsin non-catalyticchain; Serine protease hepsin catalytic chain] Q9Y663 HS3SA_HUMANHeparan sulfate glucosamine 3-O-sulfotransferase 3A1 (EC 2.8.2.30)(Heparan sulfate D- HS3ST3A1 406 glucosaminyl 3-O-sulfotransferase 3A1)(3-OST-3A) (Heparan sulfate 3-O- 3OST3A1 HS3ST3A sulfotransferase 3A1)(h3-OST-3A) UNQ2551/PRO6180 Q9Y278 HS3S2_HUMAN Heparan sulfateglucosamine 3-O-sulfotransferase 2 (EC 2.8.2.29) (Heparan sulfate D-HS3ST2 3OST2 367 glucosaminyl 3-O-sulfotransferase 2) (3-OST-2) (Heparansulfate 3-O-sulfotransferase 2) UNQ2442/PRO5004 (h3-OST-2) Q9Y661HS3S4_HUMAN Heparan sulfate glucosamine 3-O-sulfotransferase 4 (EC2.8.2.23) (Heparan sulfate D- HS3ST4 3OST4 456 glucosaminyl3-O-sulfotransferase 4) (3-OST-4) (Heparan sulfate 3-O-sulfotransferase4) (h3-OST-4) Q96QI5 HS3S6_HUMAN Heparan sulfate glucosamine3-O-sulfotransferase 6 (EC 2.8.2.23) (Heparan sulfate D- HS3ST6 HS3ST5342 glucosaminyl 3-O-sulfotransferase 6) (3-OST-6) (Heparan sulfate3-O-sulfotransferase 6) (h3-OST-6) Q9Y662 HS3SB_HUMAN Heparan sulfateglucosamine 3-O-sulfotransferase 3B1 (EC 2.8.2.30) (Heparan sulfate D-HS3ST3B1 390 glucosaminyl 3-O-sulfotransferase 3B1) (3-OST-3B) (Heparansulfate 3-O- 3OST3B1 HS3ST3B sulfotransferase 3B1) (h3-OST-3B) P07099HYEP_HUMAN Epoxide hydrolase 1 (EC 3.3.2.9) (Epoxide hydratase)(Microsomal epoxide hydrolase) EPHX1 EPHX 455 EPOX P46695 IEX1_HUMANRadiation-inducible immediate-early gene IEX-1(Differentiation-dependent gene 2 IER3 DIF2 IEX1 156 protein) (ProteinDIF-2) (Immediate early protein GLY96) (Immediate early response 3 PRG1protein) (PACAP-responsive gene 1 protein) (Protein PRG1) P55073IOD3_HUMAN Thyroxine 5-deiodinase (EC 1.21.99.3) (5DIII) (DIOIII) (Type3 DI) (Type III iodothyronine DIO3 ITDI3 TXDI3 304 deiodinase) Q9NX62IMPA3_HUMAN Inositol monophosphatase 3 (IMP 3) (IMPase 3) (EC 3.1.3.25)(EC 3.1.3.7) (Golgi 3- IMPAD1 IMPA3 359 prime phosphoadenosine 5-primephosphate 3-prime phosphatase) (Golgi-resident PAP phosphatase) (gPAPP)(Inositol monophosphatase domain-containing protein 1) (Inositol- 1(or4)-monophosphatase 3) (Myo-inositol monophosphatase A3) Q01628IFM3_HUMAN Interferon-induced transmembrane protein 3 (Dispaninsubfamily A member 2b) IFITM3 133 (DSPA2b) (Interferon-inducible protein1-8U) Q9NQX7 ITM2C_HUMAN Integral membrane protein 2C (Cerebral protein14) (Transmembrane protein BRI3) ITM2C BRI3 hucep- 267 [Cleaved into:CT-BRI3] 14 NPD018 PSEC0047 O43736 ITM2A_HUMAN Integral membrane protein2A (Protein E25) ITM2A 263 UNQ603/PRO1189 Q6NSJ0 K1161_HUMANUncharacterized family 31 glucosidase KIAA1161 (EC 3.2.1.—) KIAA1161 714Q9Y287 ITM2B_HUMAN Integral membrane protein 2B (Immature BRI2) (imBRI2)(Protein E25B) ITM2B BRI BRI2 266 (Transmembrane protein BRI) (Bri)[Cleaved into: BRI2, membrane form (Mature BRI2) (mBRI2); BRI2intracellular domain (BRI2 ICD); BRI2C, soluble form; Bri23 peptide(Bri2- 23) (ABri23) (C-terminal peptide) (P23 peptide)] Q9NZS2KLRF1_HUMAN Killer cell lectin-like receptor subfamily F member 1(Lectin-like receptor F1) (Activating KLRF1 CLEC5C ML 232 coreceptorNKp80) (C-type lectin domain family 5 member C) P23276 KELL_HUMAN Kellblood group glycoprotein (EC 3.4.24.—) (CD antigen CD238) KEL 732 Q5H943KKLC1_HUMAN Kita-kyushu lung cancer antigen 1 (KK-LC-1) (Cancer/testisantigen 83) CT83 CXorf61 113 KKLC1 Q13241 KLRD1_HUMAN Natural killercells antigen CD94 (KP43) (Killer cell lectin-like receptor subfamily DKLRD1 CD94 179 member 1) (NK cell receptor) (CD antigen CD94) Q8N3Y3LARG2_HUMAN Glycosyltransferase-like protein LARGE2 (EC 2.4.—.—)(Glycosyltransferase-like 1B) GYLTL1B LARGE2 721 [Includes:Xylosyltransferase LARGE2 (EC 2.4.2.—); Beta-1,3-glucuronyltransferasePP5656 LARGE2 (EC 2.4.1.—)] Q12918 KLRB1_HUMAN Killer cell lectin-likereceptor subfamily B member 1 (C-type lectin domain family 5 KLRB1CLEC5B 225 member B) (HNKR-P1a) (NKR-P1A) (Natural killer cell surfaceprotein P1A) (CD antigen NKRP1A CD161) Q96E93 KLRG1_HUMAN Killer celllectin-like receptor subfamily G member 1 (C-type lectin domain family15 KLRG1 CLEC15A 195 member A) (ITIM-containing receptor MAFA-L)(MAFA-like receptor) (Mast cell function- MAFA MAFAL associated antigen)Q9UIQ6 LCAP_HUMAN Leucyl-cystinyl aminopeptidase (Cystinylaminopeptidase) (EC 3.4.11.3) (Insulin- LNPEP OTASE 1025 regulatedmembrane aminopeptidase) (Insulin-responsive aminopeptidase) (IRAP)(Oxytocinase) (OTase) (Placental leucine aminopeptidase) (P-LAP)[Cleaved into: Leucyl- cystinyl aminopeptidase, pregnancy serum form]O95461 LARGE_HUMAN Glycosyltransferase-like protein LARGE1 (EC 2.4.—.—)(Acetylglucosaminyltransferase-like LARGE KIAA0609 756 1A) [Includes:Xylosyltransferase LARGE (EC 2.4.2.—); Beta-1,3-glucuronyltransferaseLARGE1 LARGE (EC 2.4.1.—)] D3W0D1 KLRF2_HUMAN Killer cell lectin-likereceptor subfamily F member 2 (Lectin-like receptor F2) (ActivatingKLRF2 207 coreceptor NKp65) Q86UP2 KTN1_HUMAN Kinectin (CG-1 antigen)(Kinesin receptor) KTN1 CG1 1357 KIAA0004 P42167 LAP2B_HUMANLamina-associated polypeptide 2, isoforms beta/gamma (Thymopoietin,isoforms TMPO LAP2 454 beta/gamma) (TP beta/gamma) (Thymopoietin-relatedpeptide isoforms beta/gamma) (TPRP isoforms beta/gamma) [Cleaved into:Thymopoietin (TP) (Splenin); Thymopentin (TP5)] Q8NES3 LFNG_HUMANBeta-1,3-N-acetylglucosaminyltransferase lunatic fringe (EC 2.4.1.222)(O-fucosylpeptide LFNG 379 3-beta-N-acetylglucosaminyltransferase)Q96AG4 LRC59_HUMAN Leucine-rich repeat-containing protein 59(Ribosome-binding protein p34) (p34) LRRC59 PRO1855 307 Q5SRI9MANEA_HUMAN Glycoprotein endo-alpha-1,2-mannosidase (Endo-alphamannosidase) MANEA 462 (Endomannosidase) (hEndo) (EC 3.2.1.130)(Mandaselin) Q5VSG8 MANEL_HUMAN Glycoproteinendo-alpha-1,2-mannosidase-like protein (EC 3.2.1.—) MANEAL 457 Q5VT66MARC1_HUMAN Mitochondrial amidoxime-reducing component 1 (mARC1) (EC1.—.—.—) (Molybdenum MARC1 MOSC1 337 cofactor sulfurase C-terminaldomain-containing protein 1) (MOSC domain-containing protein 1) (Mocosulfurase C-terminal domain-containing protein 1) Q9UKM7 MA1B1_HUMANEndoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase (EC3.2.1.113) MAN1B1 699 (ER alpha-1,2-mannosidase) (ER mannosidase 1)(ERMan1) (Man9GlcNAc2-specific- UNQ747/PRO1477 processingalpha-mannosidase) (Mannosidase alpha class 1B member 1) Q16706MA2A1_HUMAN Alpha-mannosidase 2 (EC 3.2.1.114) (Golgi alpha-mannosidaseII) (AMan II) (Man II) MAN2A1 MANA2 1144 (Mannosidase alpha class 2Amember 1) (Mannosyl-oligosaccharide 1,3-1,6-alpha- mannosidase) P49641MA2A2_HUMAN Alpha-mannosidase 2x (EC 3.2.1.114) (Alpha-mannosidase IIx)(Man IIx) (Mannosidase MAN2A2 MANA2X 1150 alpha class 2A member 2)(Mannosyl-oligosaccharide 1,3-1,6-alpha-mannosidase) P33908 MA1A1_HUMANMannosyl-oligosaccharide 1,2-alpha-mannosidase IA (EC 3.2.1.113)(Man(9)-alpha- MAN1A1 653 mannosidase) (Man9-mannosidase) (Mannosidasealpha class 1A member 1) (Processing alpha-1,2-mannosidase IA)(Alpha-1,2-mannosidase IA) O60476 MA1A2_HUMAN Mannosyl-oligosaccharide1,2-alpha-mannosidase IB (EC 3.2.1.113) (Mannosidase alpha MAN1A2 MAN1B641 class 1A member 2) (Processing alpha-1,2-mannosidase IB)(Alpha-1,2-mannosidase IB) Q9NR34 MA1C1_HUMAN Mannosyl-oligosaccharide1,2-alpha-mannosidase IC (EC 3.2.1.113) (HMIC) MAN1C1 MAN1A3 630(Mannosidase alpha class 1C member 1) (Processing alpha-1,2-mannosidaseIC) (Alpha- MAN1C 1,2-mannosidase IC) Q9UEW3 MARCO_HUMAN Macrophagereceptor MARCO (Macrophage receptor with collagenous structure) MARCOSCARA2 520 (Scavenger receptor class A member 2) O00587 MFNG_HUMANBeta-1,3-N-acetylglucosaminyltransferase manic fringe (EC 2.4.1.222)(O-fucosylpeptide MFNG 321 3-beta-N-acetylglucosaminyltransferase)Q09327 MGAT3_HUMAN Beta-1,4-mannosyl-glycoprotein4-beta-N-acetylglucosaminyltransferase (EC 2.4.1.144) MGAT3 GGNT3 533(N-glycosyl-oligosaccharide-glycoprotein N-acetylglucosaminyltransferaseIII) (GNT-III) (GlcNAc-T III) (N-acetylglucosaminyltransferase III)Q3V5L5 MGT5B_HUMAN Alpha-1,6-mannosylglycoprotein6-beta-N-acetylglucosaminyltransferase B (EC 2.4.1.—) MGAT5B KIAA2008792 (EC 2.4.1.155) (Alpha-mannosidebeta-1,6-N-acetylglucosaminyltransferase B) (GlcNAc- T Vb) (GNT-Vb)(hGnTVb) (Mannoside acetylglucosaminyltransferase 5B) (N-acetylglucosaminyl-transferase Vb) (N-acetylglucosaminyltransferase IX)(GNT-IX) Q8IX19 MCEM1_HUMAN Mast cell-expressed membrane protein 1MCEMP1 C19orf59 187 O43451 MGA_HUMAN Maltase-glucoamylase, intestinal[Includes: Maltase (EC 3.2.1.20) (Alpha-glucosidase); MGAM MGA 1857Glucoamylase (EC 3.2.1.3) (Glucan 1,4-alpha-glucosidase)] MGAML Q9UBM8MGT4C_HUMAN Alpha-1,3-mannosyl-glycoprotein4-beta-N-acetylglucosaminyltransferase C (EC MGAT4C 478 2.4.1.145)(N-acetylglucosaminyltransferase IV homolog) (hGnT-IV-H) (N-glycosyl-oligosaccharide-glycoprotein N-acetylglucosaminyltransferase IVc)(GlcNAc-T IVc) (GnT- IVc) (N-acetylglucosaminyltransferase IVc)(UDP-N-acetylglucosamine: alpha-1,3-D- mannosidebeta-1,4-N-acetylglucosaminyltransferase IVc) Q10469 MGAT2_HUMANAlpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase(EC 2.4.1.143) MGAT2 447 (Beta-1,2-N-acetylglucosaminyltransferase II)(GlcNAc-T II) (GNT-II) (Mannoside acetylglucosaminyltransferase 2)(N-glycosyl-oligosaccharide-glycoprotein N-acetylglucosaminyltransferase II) P26572 MGAT1_HUMANAlpha-1,3-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase(EC 2.4.1.101) MGAT1 GGNT1 445 (N-glycosyl-oligosaccharide-glycoproteinN-acetylglucosaminyltransferase I) (GNT-I) GLCT1 GLYT1 MGAT (GlcNAc-T I)Q9UM21 MGT4A_HUMAN Alpha-1,3-mannosyl-glycoprotein4-beta-N-acetylglucosaminyltransferase A (EC MGAT4A 535 2.4.1.145)(N-glycosyl-oligosaccharide-glycoprotein N-acetylglucosaminyltransferaseIVa) (GlcNAc-T IVa) (GnT-IVa) (N-acetylglucosaminyltransferase IVa)(UDP-N- acetylglucosamine: alpha-1,3-D-mannosidebeta-1,4-N-acetylglucosaminyltransferase IVa) [Cleaved into:Alpha-1,3-mannosyl-glycoprotein 4-beta-N- acetylglucosaminyltransferaseA soluble form] Q9UQ53 MGT4B_HUMAN Alpha-1,3-mannosyl-glycoprotein4-beta-N-acetylglucosaminyltransferase B (EC MGAT4B 548 2.4.1.145)(N-glycosyl-oligosaccharide-glycoprotein N-acetylglucosaminyltransferaseIVb) UNQ906/PRO1927 (GlcNAc-T IVb) (GnT-IVb)(N-acetylglucosaminyltransferase IVb) (UDP-N- acetylglucosamine:alpha-1,3-D-mannoside beta-1,4-N-acetylglucosaminyltransferase IVb)Q9BY79 MFRP_HUMAN Membrane frizzled-related protein (Membrane-typefrizzled-related protein) MFRP 579 Q495T6 MMEL1_HUMAN Membranemetallo-endopeptidase-like 1 (EC 3.4.24.11) (Membrane metallo- MMEL1MELL1 779 endopeptidase-like 2) (NEP2(m)) (Neprilysin II) (NEPII)(Neprilysin-2) (NEP2) (NL2) MMEL2 NEP2 [Cleaved into: Membranemetallo-endopeptidase-like 1, soluble form (Neprilysin-2 secreted)(NEP2(s))] O75900 MMP23_HUMAN Matrix metalloproteinase-23 (MMP-23) (EC3.4.24.—) (Femalysin) (MIFR-1) (Matrix MMP23A MMP21; 390metalloproteinase-21) (MMP-21) (Matrix metalloproteinase-22) (MMP-22)[Cleaved into: MMP23B MMP21 Matrix metalloproteinase-23, soluble form]MMP22 Q09328 MGT5A_HUMAN Alpha-1,6-mannosylglycoprotein6-beta-N-acetylglucosaminyltransferase A (EC MGAT5 GGNT5 741 2.4.1.155)(Alpha-mannoside beta-1,6-N-acetylglucosaminyltransferase) (GlcNAc-T V)(GNT-V) (Mannoside acetylglucosaminyltransferase 5)(N-acetylglucosaminyl-transferase V) Q13724 MOGS_HUMANMannosyl-oligosaccharide glucosidase (EC 3.2.1.106) (ProcessingA-glucosidase I) MOGS GCS1 837 P21757 MSRE_HUMAN Macrophage scavengerreceptor types I and II (Macrophage acetylated LDL receptor I MSR1SCARA1 451 and II) (Scavenger receptor class A member 1) (CD antigenCD204) Q9NZM1 MYOF_HUMAN Myoferlin (Fer-1-like protein 3) MYOF FER1L32061 KIAA1207 Q58DX5 NADL2_HUMAN Inactive N-acetylated-alpha-linkedacidic dipeptidase-like protein 2 (NAALADase L2) NAALADL2 795 Q9Y3Q0NALD2_HUMAN N-acetylated-alpha-linked acidic dipeptidase 2 (EC3.4.17.21) (Glutamate NAALAD2 740 carboxypeptidase III) (GCPIII)(N-acetylated-alpha-linked acidic dipeptidase II) (NAALADase II) O95803NDST3_HUMAN Bifunctional heparan sulfateN-deacetylase/N-sulfotransferase 3 (EC 2.8.2.8) NDST3 HSST3 873(Glucosaminyl N-deacetylase/N-sulfotransferase 3) (NDST-3) (hNDST-3)(N-heparan UNQ2544/PRO4998 sulfate sulfotransferase 3) (N-HSST 3)[Includes: Heparan sulfate N-deacetylase 3 (EC 3.—.—.—); Heparan sulfateN-sulfotransferase 3 (EC 2.8.2.—)] Q9UQQ1 NALDL_HUMANN-acetylated-alpha-linked acidic dipeptidase-like protein (NAALADase L)(EC 3.4.17.21) NAALADL1 740 (100 kDa ileum brush border membraneprotein) (I100) (Ileal dipeptidylpeptidase) NAALADASEL NAALADL Q9UHE5NAT8_HUMAN N-acetyltransferase 8 (EC 2.3.1.—) (Acetyltransferase 2)(ATase2) (Camello-like protein 1) NAT8 CML1 GLA 227 (Cysteinyl-conjugateN-acetyltransferase) (CCNAT) (EC 2.3.1.80) TSC501 Q6PIU2 NCEH1_HUMANNeutral cholesterol ester hydrolase 1 (NCEH) (EC 3.1.1.—) (Arylacetamidedeacetylase- NCEH1 AADACL1 408 like 1) KIAA1363 P52848 NDST1_HUMANBifunctional heparan sulfate N-deacetylase/N-sulfotransferase 1 (EC2.8.2.8) NDST1 HSST 882 (GlucosaminylN-deacetylase/N-sulfotransferase 1) (NDST-1) (N-heparan sulfate HSST1sulfotransferase 1) (N-HSST 1) ([Heparan sulfate]-glucosamineN-sulfotransferase 1) (HSNST 1) [Includes: Heparan sulfate N-deacetylase1 (EC 3.—.—.—); Heparan sulfate N- sulfotransferase 1 (EC 2.8.2.—)]P52849 NDST2_HUMAN Bifunctional heparan sulfateN-deacetylase/N-sulfotransferase 2 (EC 2.8.2.8) NDST2 HSST2 883(Glucosaminyl N-deacetylase/N-sulfotransferase 2) (NDST-2) (N-heparansulfate sulfotransferase 2) (N-HSST 2) [Includes: Heparan sulfateN-deacetylase 2 (EC 3.—.—.—); Heparan sulfate N-sulfotransferase 2 (EC2.8.2.—)] Q9H3R1 NDST4_HUMAN Bifunctional heparan sulfateN-deacetylase/N-sulfotransferase 4 (EC 2.8.2.8) NDST4 HSST4 872(Glucosaminyl N-deacetylase/N-sulfotransferase 4) (NDST-4) (N-heparansulfate sulfotransferase 4) (N-HSST 4) [Includes: Heparan sulfateN-deacetylase 4 (EC 3.—.—.—); Heparan sulfate N-sulfotransferase 4 (EC2.8.2.—)] P26717 NKG2C_HUMAN NKG2-C type II integral membrane protein(CD159 antigen-like family member C) (NK KLRC2 NKG2C 231 cell receptorC) (NKG2-C-activating NK receptor) (CD antigen CD159c) P26718NKG2D_HUMAN NKG2-D type II integral membrane protein (Killer celllectin-like receptor subfamily K KLRK1 D12S2489E 216 member 1) (NK cellreceptor D) (NKG2-D-activating NK receptor) (CD antigen CD314) NKG2DQ9UHF3 NAT8B_HUMAN Putative N-acetyltransferase 8B (EC 2.3.1.—)(Acetyltransferase 1) (ATase1) (Camello-like NAT8B CML2 227 protein 2)P08473 NEP_HUMAN Neprilysin (EC 3.4.24.11) (Atriopeptidase) (Commonacute lymphocytic leukemia antigen) MME EPN 750 (CALLA) (Enkephalinase)(Neutral endopeptidase 24.11) (NEP) (Neutral endopeptidase) (Skinfibroblast elastase) (SFE) (CD antigen CD10) P26715 NKG2A_HUMANNKG2-A/NKG2-B type II integral membrane protein (CD159 antigen-likefamily member KLRC1 NKG2A 233 A) (NK cell receptor A)(NKG2-A/B-activating NK receptor) (CD antigen CD159a) Q14494 NF2L1_HUMANNuclear factor erythroid 2-related factor 1 (NF-E2-related factor 1)(NFE2-related factor 1) NFE2L1 HBZ17 772 (Locus control region-factor 1)(Nuclear factor, erythroid derived 2, like 1) (Transcription NRF1 TCF11factor 11) (TCF-11) (Transcription factor HBZ17) (Transcription factorLCR-F1) O43908 NKG2F_HUMAN NKG2-F type II integral membrane protein (NKcell receptor F) (NKG2-F-activating NK KLRC4 NKG2F 158 receptor) P42857NSG1_HUMAN Neuron-specific protein family member 1 (Brain neuroncytoplasmic protein 1) NSG1 D4S234 185 Q07444 NKG2E_HUMAN NKG2-E type IIintegral membrane protein (NK cell receptor E) (NKG2-E-activating NKKLRC3 NKG2E 240 receptor) Q9Y328 NSG2_HUMAN Neuron-specific proteinfamily member 2 (Protein p19) (Hmp19) NSG2 171 O95502 NPTXR_HUMANNeuronal pentraxin receptor NPTXR 500 Q6PK18 OGFD3_HUMAN 2-oxoglutarateand iron-dependent oxygenase domain-containing protein 3 (EC 1.14.11.—)OGFOD3 C17orf101 319 Q9NXG6 P4HTM_HUMAN Transmembrane prolyl4-hydroxylase (P4H-TM) (EC 1.14.11.—) (Hypoxia-inducible factor P4HTMPH4 502 prolyl hydroxylase 4) (HIF-PH4) (HIF-prolyl hydroxylase 4)(HPH-4) Q9HC10 OTOF_HUMAN Otoferlin (Fer-1-like protein 2) OTOF FER1L21997 P78380 OLR1_HUMAN Oxidized low-density lipoprotein receptor 1(Ox-LDL receptor 1) (C-type lectin domain OLR1 CLEC8A 273 family 8member A) (Lectin-like oxidized LDL receptor 1) (LOX-1) (Lectin-likeoxLDL LOX1 receptor 1) (hLOX-1) (Lectin-type oxidized LDL receptor 1)[Cleaved into: Oxidized low- density lipoprotein receptor 1, solubleform] Q8NF37 PCAT1_HUMAN Lysophosphatidylcholine acyltransferase 1 (LPCacyltransferase 1) (LPCAT-1) (LysoPC LPCAT1 AYTL2 534 acyltransferase 1)(EC 2.3.1.23) (1-acylglycerophosphocholine O-acyltransferase) (1- PFAAP3alkylglycerophosphocholine O-acetyltransferase) (EC 2.3.1.67)(Acetyl-CoA: lyso-platelet- activating factor acetyltransferase)(Acetyl-CoA: lyso-PAF acetyltransferase) (Lyso-PAF acetyltransferase)(LysoPAFAT) (Acyltransferase-like 2) (Phosphonoformate immuno-associated protein 3) Q7L5N7 PCAT2_HUMAN Lysophosphatidylcholineacyltransferase 2 (LPC acyltransferase 2) (LPCAT-2) (LysoPC LPCAT2AGPAT11 544 acyltransferase 2) (EC 2.3.1.23) (1-acylglycerol-3-phosphateO-acyltransferase 11) (1- AYTL1 AGP acyltransferase 11) (1-AGPAT 11) (EC2.3.1.51) (1-acylglycerophosphocholine O- acyltransferase)(1-alkylglycerophosphocholine O-acetyltransferase) (EC 2.3.1.67)(Acetyl-CoA: lyso-platelet-activating factor acetyltransferase)(Acetyl-CoA: lyso-PAF acetyltransferase) (Lyso-PAF acetyltransferase)(LysoPAFAT) (Acyltransferase-like 1) (Lysophosphatidic acidacyltransferase alpha) (LPAAT-alpha) Q7Z412 PEX26_HUMAN Peroxisomeassembly protein 26 (Peroxin-26) PEX26 305 Q9NST1 PLPL3_HUMANPatatin-like phospholipase domain-containing protein 3 (EC 3.1.1.3)(Acylglycerol O- PNPLA3 ADPN 481 acyltransferase) (EC 2.3.1.—)(Adiponutrin) (Calcium-independent phospholipase A2- C22orf20 epsilon)(iPLA2-epsilon) Q9NRQ2 PLS4_HUMAN Phospholipid scramblase 4 (PLscramblase 4) (Ca(2+)-dependent phospholipid PLSCR4 GIG43 329 scramblase4) (Cell growth-inhibiting gene 43 protein) (TRA1) P78562 PHEX_HUMANPhosphate-regulating neutral endopeptidase (EC 3.4.24.—)(Metalloendopeptidase PHEX PEX 749 homolog PEX) (Vitamin D-resistanthypophosphatemic rickets protein) (X-linked hypophosphatemia protein)(HYP) O15162 PLS1_HUMAN Phospholipid scramblase 1 (PL scramblase 1)(Ca(2+)-dependent phospholipid PLSCR1 318 scramblase 1) (Erythrocytephospholipid scramblase) (MmTRA1b) Q8NAT1 PMGT2_HUMAN ProteinO-linked-mannose beta-1,4-N-acetylglucosaminyltransferase 2 (POMGnT2)(EC POMGNT2 AGO61 580 2.4.1.—) (Extracellular O-linkedN-acetylglucosamine transferase-like) C3orf39 EOGTL(Glycosyltransferase-like domain-containing protein 2) GTDC2 Q8IV08PLD3_HUMAN Phospholipase D3 (PLD 3) (EC 3.1.4.4) (Choline phosphatase 3)(HindIII K4L homolog) PLD3 490 (Hu-K4) (Phosphatidylcholine-hydrolyzingphospholipase D3) Q9NRY6 PLS3_HUMAN Phospholipid scramblase 3 (PLscramblase 3) (Ca(2+)-dependent phospholipid PLSCR3 295 scramblase 3)Q9NRY7 PLS2_HUMAN Phospholipid scramblase 2 (PL scramblase 2)(Ca(2+)-dependent phospholipid PLSCR2 297 scramblase 2) Q96AD5PLPL2_HUMAN Patatin-like phospholipase domain-containing protein 2 (EC3.1.1.3) (Adipose triglyceride PNPLA2 ATGL 504 lipase)(Calcium-independent phospholipase A2) (Desnutrin) (IPLA2-zeta) (PigmentFP17548 epithelium-derived factor) (TTS2.2) (Transport-secretion protein2) (TTS2) Q9BX97 PLVAP_HUMAN Plasmalemma vesicle-associated protein(Fenestrated endothelial-linked structure PLVAP FELS PV1 442 protein)(Plasmalemma vesicle protein 1) (PV-1) Q8WZA1 PMGT1_HUMAN ProteinO-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGnTI)(EC POMGNT1 660 2.4.1.—) (UDP-GlcNAc: alpha-D-mannosidebeta-1,2-N-acetylglucosaminyltransferase I.2) MGAT1.2 (GnT I.2)UNQ746/PRO1475 Q8TE99 PXYP1_HUMAN 2-phosphoxylose phosphatase 1 (EC3.1.3.—) (Acid phosphatase-like protein 2) (Xylosyl PXYLP1 ACPL2 480phosphatase) (epididymis luminal protein 124) HEL124 XYLP UNQ370/PRO706Q8TC12 RDH11_HUMAN Retinol dehydrogenase 11 (EC 1.1.1.300)(Androgen-regulated short-chain RDH11 ARSDR1 318dehydrogenase/reductase 1) (HCV core-binding protein HCBP12) (Prostateshort-chain PSDR1 SDR7C1 dehydrogenase/reductase 1) (Retinalreductase 1) (RalR1) (Short chain CGI-82 dehydrogenase/reductase family7C member 1) Q9Y644 RFNG_HUMAN Beta-1,3-N-acetylglucosaminyltransferaseradical fringe (EC 2.4.1.222) (O-fucosylpeptide RFNG 3313-beta-N-acetylglucosaminyltransferase) Q6AZY7 SCAR3_HUMAN Scavengerreceptor class A member 3 (Cellular stress response gene protein) SCARA3CSR 606 Q6ZMJ2 SCAR5_HUMAN Scavenger receptor class A member 5(Scavenger receptor hIg) SCARA5 495 UNQ2938/PRO28700 P67812 SC11A_HUMANSignal peptidase complex catalytic subunit SEC11A (EC 3.4.21.89)(Endopeptidase SEC11A SEC11L1 179 SP18) (Microsomal signal peptidase 18kDa subunit) (SPase 18 kDa subunit) (SEC11 SPC18 SPCS4A homolog A)(SEC11-like protein 1) (SPC18) Q9BY50 SC11C_HUMAN Signal peptidasecomplex catalytic subunit SEC11C (EC 3.4.21.89) (Microsomal signalSEC11C SEC11L3 192 peptidase 21 kDa subunit) (SPase 21 kDa subunit)(SEC11 homolog C) (SEC11-like SPC21 SPCS4C protein 3) (SPC21) Q8IXA5SACA3_HUMAN Sperm acrosome membrane-associated protein 3 (Cancer/testisantigen 54) (CT54) SPACA3 LYC3 215 (Lysozyme-like acrosomalsperm-specific secretory protein ALLP-17) (Lysozyme-like LYZL3 SLLP1protein 3) (Sperm lysozyme-like protein 1) (Sperm protein reactive withantisperm SPRASA antibodies) (Sperm protein reactive with ASA) [Cleavedinto: Sperm acrosome UNQ424/PRO862 membrane-associated protein 3,membrane form; Sperm acrosome membrane- associated protein 3, processedform] P0C7V7 SC11B_HUMAN Putative signal peptidase complex catalyticsubunit SEC11B (EC 3.4.21.89) (SEC11 SEC11B SEC11L2 166 homolog B)(SEC11-like protein 2) SPCS4B Q9NSC7 SIA7A_HUMANAlpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 1 (EC2.4.99.3) (GalNAc ST6GALNAC1 SIAT7A 600 alpha-2,6-sialyltransferase I)(ST6GalNAc I) (ST6GalNAcI) (Sialyltransferase 7A) (SIAT7-A)UNQ543/PRO848 Q9H4F1 SIA7D_HUMANAlpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3-N-acetyl-galactosaminidealpha-2,6- ST6GALNAC4 302 sialyltransferase (EC 2.4.99.7)(NeuAc-alpha-2,3-Gal-beta-1,3-GalNAc-alpha-2,6- SIAT3C SIAT7Dsialyltransferase) (ST6GalNAc IV) (ST6GalNAcIV) (Sialyltransferase 3C)(SIAT3-C) (Sialyltransferase 7D) (SIAT7-D) Q92186 SIA8B_HUMANAlpha-2,8-sialyltransferase 8B (EC 2.4.99.—) (Sialyltransferase 8B)(SIAT8-B) ST8SIA2 SIAT8B 375 (Sialyltransferase St8Sia II) (ST8SiaII)(Sialyltransferase X) (STX) STX P15907 SIAT1_HUMAN Beta-galactosidealpha-2,6-sialyltransferase 1 (Alpha 2,6-ST 1) (EC 2.4.99.1) (B-cellST6GAL1 SIAT1 406 antigen CD75)(CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,6-sialyltransferase 1) (ST6Gal I) (ST6GalI) (Sialyltransferase 1) Q16585SGCB_HUMAN Beta-sarcoglycan (Beta-SG) (43 kDa dystrophin-associatedglycoprotein) (43DAG) (A3b) SGCB 318 Q13326 SGCG_HUMAN Gamma-sarcoglycan(Gamma-SG) (35 kDa dystrophin-associated glycoprotein) (35DAG) SGCG 291Q96LD1 SGCZ_HUMAN Zeta-sarcoglycan (Zeta-SG) (ZSG1) SGCZ 299 Q92185SIA8A_HUMAN Alpha-N-acetylneuraminide alpha-2,8-sialyltransferase (EC2.4.99.8) (Alpha-2,8- ST8SIA1 SIAT8 SIAT8A 356 sialyltransferase 8A)(Ganglioside GD3 synthase) (Ganglioside GT3 synthase) (Sialyltransferase8A) (SIAT8-A) (Sialyltransferase St8Sia I) (ST8SiaI) Q92187 SIA8D_HUMANCMP-N-acetylneuraminate-poly-alpha-2,8-sialyltransferase (EC 2.4.99.—)(Alpha-2,8- ST8SIA4 PST PST1 359 sialyltransferase 8D)(Polysialyltransferase-1) (Sialyltransferase 8D) (SIAT8-D) SIAT8D(Sialyltransferase St8Sia IV) (ST8SiaIV) P61647 SIA8F_HUMANAlpha-2,8-sialyltransferase 8F (EC 2.4.99.—) (Sialyltransferase 8F)(SIAT8-F) ST8SIA6 SIAT8F 398 (Sialyltransferase St8Sia VI) (ST8SiaVI)Q96JF0 SIAT2_HUMAN Beta-galactoside alpha-2,6-sialyltransferase 2 (Alpha2,6-ST 2) (EC 2.4.99.1) (CMP-N- ST6GAL2 KIAA1877 529acetylneuraminate-beta-galactosamide-alpha-2,6-sialyltransferase 2)(ST6Gal II) SIAT2 (ST6GalII) (hST6Gal II) (Sialyltransferase 2) A6NLE4SIM23_HUMAN Small integral membrane protein 23 SMIM23 C5orf50 156 Q07837SLC31_HUMAN Neutral and basic amino acid transport protein rBAT (NBAT)(D2h) (Solute carrier family 3 SLC3A1 RBAT 685 member 1) (b(0, +)-typeamino acid transport protein) O43173 SIA8C_HUMANSia-alpha-2,3-Gal-beta-1,4-GlcNAc-R: alpha 2,8-sialyltransferase (EC2.4.99.—) (Alpha- ST8SIA3 SIAT8C 380 2,8-sialyltransferase 8C)(Alpha-2,8-sialyltransferase III) (ST8 alpha-N-acetyl- neuraminidealpha-2,8-sialyltransferase 3) (Sialyltransferase 8C) (SIAT8-C)(Sialyltransferase St8Sia III) (ST8SiaIII) Q11201 SIA4A_HUMANCMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1(Alpha 2,3- ST3GAL1 SIAT4 340 ST 1) (Beta-galactosidealpha-2,3-sialyltransferase 1) (EC 2.4.99.4) (Gal-NAc6S) (Gal- SIAT4Abeta-1,3-GalNAc-alpha-2,3-sialyltransferase) (SIATFL) (ST3Gal I)(ST3GalI) (ST3GalA.1) (ST3O) (Sialyltransferase 4A) (SIAT4-A) Q969X2SIA7F_HUMAN Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 6(EC 2.4.99.—) (GalNAc ST6GALNAC6 SIAT7F 333 alpha-2,6-sialyltransferaseVI) (ST6GalNAc VI) (ST6GalNAcVI) (hST6GalNAc VI) UNQ708/PRO1359(Sialyltransferase 7F) (SIAT7-F) Q9UNP4 SIAT9_HUMAN Lactosylceramidealpha-2,3-sialyltransferase (EC 2.4.99.9) (CMP- ST3GAL5 SIAT9 418 NeuAc:lactosylceramide alpha-2,3-sialyltransferase) (Ganglioside GM3 synthase)UNQ2510/PRO5998 (STSGal V) (STSGalV) (Sialyltransferase 9) Q9H5K3SG196_HUMAN Protein O-mannose kinase (POMK) (EC 2.7.1.183) (Proteinkinase-like protein SgK196) POMK SGK196 350 (Sugen kinase 196) Q9Y274SIA10_HUMAN Type 2 lactosamine alpha-2,3-sialyltransferase (EC 2.4.99.—)(CMP-NeuAc: beta- ST3GAL6 SIAT10 331 galactosidealpha-2,3-sialyltransferase VI) (ST3Gal VI) (ST3GalVI)(Sialyltransferase 10) Q16842 SIA4B_HUMANCMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 2(Alpha 2,3- ST3GAL2 SIAT4B 350 ST 2) (Beta-galactosidealpha-2,3-sialyltransferase 2) (EC 2.4.99.4) (Gal-NAc6S) (Gal-beta-1,3-GalNAc-alpha-2,3-sialyltransferase) (ST3Gal II) (ST3GalII)(ST3GalA.2) (Sialyltransferase 4B) (SIAT4-B) Q11206 SIA4C_HUMANCMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 4(Alpha 2,3- ST3GAL4 CGS23 333 ST 4) (Beta-galactosidealpha-2,3-sialyltransferase 4) (EC 2.4.99.—) (Alpha 2,3- NANTA3 SIAT4Csialyltransferase IV) (Gal-NAc6S)(Gal-beta-1,4-GalNAc-alpha-2,3-sialyltransferase) STZ (SAT-3) (ST-4)(ST3Gal IV) (ST3GalIV) (ST3GalA.2) (STZ) (Sialyltransferase 4C)(SIAT4-C) Q9UJ37 SIA7B_HUMAN Alpha-N-acetylgalactosaminidealpha-2,6-sialyltransferase 2 (EC 2.4.99.—) (GalNAc ST6GALNAC2 374alpha-2,6-sialyltransferase II) (ST6GalNAc II) (ST6GalNAcII) (SThM)(Sialyltransferase SIAT7B SIATL1 7B) (SIAT7-B) STHM Q9BVH7 SIA7E_HUMANAlpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 5 (EC2.4.99.—) (GD1 alpha ST6GALNAC5 336 synthase) (GalNAcalpha-2,6-sialyltransferase V) (ST6GalNAc V) (ST6GalNAcV) SIAT7E(Sialyltransferase 7E) (SIAT7-E) Q11203 SIAT6_HUMANCMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase(EC 2.4.99.6) ST3GAL3 SIAT6 375 (Beta-galactosidealpha-2,3-sialyltransferase 3) (Alpha 2,3-ST 3) (Gal beta-1,3(4) GlcNAcalpha-2,3 Sialyltransferase) (N-acetyllactosaminidealpha-2,3-sialyltransferase) (ST3Gal III) (STSGalIII) (ST3N)(Sialyltransferase 6) Q12884 SEPR_HUMAN Prolyl endopeptidase FAP (EC3.4.21.26) (170 kDa melanoma membrane-bound FAP 760 gelatinase)(Dipeptidyl peptidase FAP) (EC 3.4.14.5) (Fibroblast activation proteinalpha) (FAPalpha) (Gelatine degradation protease FAP) (EC 3.4.21.—)(Integral membrane serine protease) (Post-proline cleaving enzyme)(Serine integral membrane protease) (SIMP) (Surface-expressed protease)(Seprase) [Cleaved into: Antiplasmin-cleaving enzyme FAP, soluble form(APCE) (EC 3.4.14.5) (EC 3.4.21.—) (EC 3.4.21.26)] Q8NDV1 SIA7C_HUMANAlpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 3 (EC2.4.99.—) (GalNAc ST6GALNAC3 305 alpha-2,6-sialyltransferase III)(ST6GalNAc III) (ST6GalNAcIII) (STY) (Sialyltransferase SIAT7C 7C)(SIAT7-C) UNQ2787/PRO7177 O15466 SIA8E_HUMAN Alpha-2,8-sialyltransferase8E (EC 2.4.99.—) (Sialyltransferase 8E) (SIAT8-E) ST8SIA5 SIAT8E 376(Sialyltransferase St8Sia V) (ST8SiaV) Q92629 SGCD_HUMANDelta-sarcoglycan (Delta-SG) (35 kDa dystrophin-associated glycoprotein)(35DAG) SGCD 289 Q86WD7 SPA9_HUMAN Serpin A9 (Centerin) (Germinal centerB-cell-expressed transcript 1 protein) SERPINA9 GCET1 417 SERPINA11UNQ692/PRO1337 P61009 SPCS3_HUMAN Signal peptidase complex subunit 3 (EC3.4.—.—) (Microsomal signal peptidase 22/23 kDa SPCS3 SPC22 180 subunit)(SPC22/23) (SPase 22/23 kDa subunit) UNQ1841/PRO3567 Q9UH99 SUN2_HUMANSUN domain-containing protein 2 (Protein unc-84 homolog B)(Rab5-interacting protein) SUN2 FRIGG 717 (Rab5IP) (Sad1/unc-84protein-like 2) KIAA0668 RAB5IP UNC84B Q9Y5Y6 ST14_HUMAN Suppressor oftumorigenicity 14 protein (EC 3.4.21.109) (Matriptase) (Membrane-typeST14 PRSS14 855 serine protease 1) (MT-SP1) (Prostamin) (Serine protease14) (Serine protease TADG- SNC19 TADG15 15) (Tumor-associateddifferentially-expressed gene 15 protein) P14410 SUIS_HUMANSucrase-isomaltase, intestinal [Cleaved into: Sucrase (EC 3.2.1.48);Isomaltase (EC 3.2.1.10)] SI 1827 O94901 SUN1_HUMAN SUNdomain-containing protein 1 (Protein unc-84 homolog A) (Sad1/unc-84protein-like 1) SUN1 KIAA0810 812 UNC84A Q9NUM4 T106B_HUMANTransmembrane protein 106B TMEM106B 274 Q9H7V2 SYNG1_HUMAN Synapsedifferentiation-inducing gene protein 1 (SynDIG1) (Dispanin subfamily CSYNDIG1 C20orf39 258 member 2) (DSPC2) (Transmembrane protein 90B)TMEM90B P02786 TFR1_HUMAN Transferrin receptor protein 1 (TR) (TfR)(TfR1) (Trfr) (T9) (p90) (CD antigen CD71) TFRC 760 [Cleaved into:Transferrin receptor protein 1, serum form (sTfR)] Q9UP52 TFR2_HUMANTransferrin receptor protein 2 (TfR2) TFR2 801 Q9NRS4 TMPS4_HUMANTransmembrane protease serine 4 (EC 3.4.21.—) (Channel-activatingprotease 2) TMPRSS4 437 (CAPH2) (Membrane-type serine protease 2)(MT-SP2) TMPRSS3 UNQ776/PRO1570 P50591 TNF10_HUMAN Tumor necrosis factorligand superfamily member 10 (Apo-2 ligand) (Apo-2L) (TNF- TNFSF10 APO2L281 related apoptosis-inducing ligand) (Protein TRAIL) (CD antigenCD253) TRAIL O43508 TNF12_HUMAN Tumor necrosis factor ligand superfamilymember 12 (APO3 ligand) (TNF-related weak TNFSF12 APO3L 249 inducer ofapoptosis) (TWEAK) [Cleaved into: Tumor necrosis factor ligandsuperfamily DR3LG member 12, membrane form; Tumor necrosis factor ligandsuperfamily member 12, UNQ181/PRO207 secreted form] Q06643 TNFC_HUMANLymphotoxin-beta (LT-beta) (Tumor necrosis factor C) (TNF-C) (Tumornecrosis factor LTB TNFC TNFSF3 244 ligand superfamily member 3) P41273TNFL9_HUMAN Tumor necrosis factor ligand superfamily member 9 (4-1BBligand) (4-1BBL) TNFSF9 254 Q6ZMR5 TM11A_HUMAN Transmembrane proteaseserine 11A (EC 3.4.21.—) (Airway trypsin-like protease 1) TMPRSS11A 421(Epidermal type-II transmembrane serine protease) (Esophagealcancer-susceptibility ECRG1 HATL1 gene 1 protein) HESP Q6ZWK6TM11F_HUMAN Transmembrane protease serine 11F (EC 3.4.21.—) (Airwaytrypsin-like protease 4) TMPRSS11F HATL4 438 P23510 TNFL4_HUMAN Tumornecrosis factor ligand superfamily member 4 (Glycoprotein Gp34) (OX40ligand) TNFSF4 TXGP1 183 (OX40L) (TAX transcriptionally-activatedglycoprotein 1) (CD antigen CD252) P01375 TNFA_HUMAN Tumor necrosisfactor (Cachectin) (TNF-alpha) (Tumor necrosis factor ligand superfamilyTNF TNFA TNFSF2 233 member 2) (TNF-a) [Cleaved into: Tumor necrosisfactor, membrane form (N-terminal fragment) (NTF); Intracellular domain1 (ICD1); Intracellular domain 2 (ICD2); C-domain 1; C-domain 2; Tumornecrosis factor, soluble form] O15393 TMPS2_HUMAN Transmembrane proteaseserine 2 (EC 3.4.21.—) (Serine protease 10) [Cleaved into: TMPRSS2PRSS10 492 Transmembrane protease serine 2 non-catalytic chain;Transmembrane protease serine 2 catalytic chain] Q9H3S3 TMPS5_HUMANTransmembrane protease serine 5 (EC 3.4.21.—) (Spinesin) TMPRSS5 457Q7RTY8 TMPS7_HUMAN Transmembrane protease serine 7 (EC 3.4.21.—)(Matriptase-3) TMPRSS7 843 O43557 TNF14_HUMAN Tumor necrosis factorligand superfamily member 14 (Herpes virus entry mediator ligand)TNFSF14 HVEML LIGHT 240 (HVEM-L) (Herpesvirus entry mediator ligand) (CDantigen CD258) [Cleaved into: Tumor UNQ391/PRO726 necrosis factor ligandsuperfamily member 14, membrane form; Tumor necrosis factor ligandsuperfamily member 14, soluble form] P48023 TNFL6_HUMAN Tumor necrosisfactor ligand superfamily member 6 (Apoptosis antigen ligand) (APTL)FASLG APT1LG1 281 (CD95 ligand) (CD95-L) (Fas antigen ligand) (Fasligand) (FasL) (CD antigen CD178) CD95L FASL [Cleaved into: Tumornecrosis factor ligand superfamily member 6, membrane form; TNFSF6 Tumornecrosis factor ligand superfamily member 6, soluble form(Receptor-binding FasL ectodomain) (Soluble Fas ligand) (sFasL);ADAM10-processed FasL form (APL); FasL intracellular domain (FasL ICD)(SPPL2A-processed FasL form) (SPA)] Q86T26 TM11B_HUMAN Transmembraneprotease serine 11B (EC 3.4.21.—) (Airway trypsin-like protease 5)TMPRSS11B 416 HATL5 O95150 TNF15_HUMAN Tumor necrosis factor ligandsuperfamily member 15 (TNF ligand-related molecule 1) TNFSF15 TL1 VEGI251 (Vascular endothelial cell growth inhibitor) [Cleaved into: Tumornecrosis factor ligand superfamily member 15, membrane form; Tumornecrosis factor ligand superfamily member 15, secreted form] Q9UL52TM11E_HUMAN Transmembrane protease serine 11E (EC 3.4.21.—) (Serineprotease DESC1) TMPRSS11E 423 (Transmembrane protease serine 11E2)[Cleaved into: Transmembrane protease serine DESC1 11E non-catalyticchain; Transmembrane protease serine 11E catalytic chain] TMPRSS11E2UNQ742/PRO1461 Q8IU80 TMPS6_HUMAN Transmembrane protease serine 6 (EC3.4.21.—) (Matriptase-2) TMPRSS6 811 UNQ354/PRO618 Q7Z410 TMPS9_HUMANTransmembrane protease serine 9 (EC 3.4.21.—) (Polyserase-I) (Polyserineprotease 1) TMPRSS9 1059 (Polyserase-1) [Cleaved into: Serase-1;Serase-2; Serase-3] Q9BYE2 TMPSD_HUMAN Transmembrane protease serine 13(EC 3.4.21.—) (Membrane-type mosaic serine TMPRSS13 MSP 586 protease)(Mosaic serine protease) TMPRSS11 O14788 TNF11_HUMAN Tumor necrosisfactor ligand superfamily member 11 (Osteoclast differentiation factor)TNFSF11 OPGL 317 (ODF) (Osteoprotegerin ligand) (OPGL) (Receptoractivator of nuclear factor kappa-B RANKL TRANCE ligand) (RANKL)(TNF-related activation-induced cytokine) (TRANCE) (CD antigen CD254)[Cleaved into: Tumor necrosis factor ligand superfamily member 11,membrane form; Tumor necrosis factor ligand superfamily member 11,soluble form] O60507 TPST1_HUMAN Protein-tyrosine sulfotransferase 1 (EC2.8.2.20) (Tyrosylprotein sulfotransferase 1) TPST1 370 (TPST-1) O60235TM11D_HUMAN Transmembrane protease serine 11D (EC 3.4.21.—) (Airwaytrypsin-like protease) TMPRSS11D HAT 418 [Cleaved into: Transmembraneprotease serine 11D non-catalytic chain; Transmembrane protease serine11D catalytic chain] Q9Y2B1 TMEM5_HUMAN Transmembrane protein 5 TMEM5443 P57727 TMPS3_HUMAN Transmembrane protease serine 3 (EC 3.4.21.—)(Serine protease TADG-12) (Tumor- TMPRSS3 ECHOS1 454 associateddifferentially-expressed gene 12 protein) TADG12 UNQ323/PRO382 Q9Y275TN13B_HUMAN Tumor necrosis factor ligand superfamily member 13B (Blymphocyte stimulator) (BLyS) TNFSF13B BAFF 285 (B-cell-activatingfactor) (BAFF) (Dendritic cell-derived TNF-like molecule) (TNF- and BLYSTALL1 APOL-related leukocyte expressed ligand 1) (TALL-1) (CD antigenCD257) [Cleaved into: TNFSF20 ZTNF4 Tumor necrosis factor ligandsuperfamily member 13b, membrane form; Tumor necrosis UNQ401/PRO738factor ligand superfamily member 13b, soluble form] P32971 TNFL8_HUMANTumor necrosis factor ligand superfamily member 8 (CD30 ligand) (CD30-L)(CD antigen CD153) TNFSF8 CD30L CD30LG 234 Q13061 TRDN_HUMAN TriadinTRDN 729 Q9UNG2 TNF18_HUMAN Tumor necrosis factor ligand superfamilymember 18 (Activation-inducible TNF-related TNFSF18 AITRL 199 ligand)(AITRL) (Glucocorticoid-induced TNF-related ligand) (hGITRL) GITRL TL6UNQ149/PRO175 Q9H2S6 TNMD_HUMAN Tenomodulin (TeM) (hTeM)(Chondromodulin-1-like protein) (ChM1L) (hChM1L) TNMD CHM1L 317(Chondromodulin-I-like protein) (Myodulin) (Tendin) UNQ771/PRO1565O60704 TPST2_HUMAN Protein-tyrosine sulfotransferase 2 (EC 2.8.2.20)(Tyrosylprotein sulfotransferase 2) (TPST-2) TPST2 377 Q9UKU6TRHDE_HUMAN Thyrotropin-releasing hormone-degrading ectoenzyme (TRH-DE)(TRH-degrading TRHDE 1024 ectoenzyme) (EC 3.4.19.6)(Pyroglutamyl-peptidase II) (PAP-II) (TRH-specific UNQ2507/PRO5995aminopeptidase) (Thyroliberinase) Q9Y2C2 UST_HUMAN Uronyl2-sulfotransferase (EC 2.8.2.—) UST DS2ST 406 Q8NBZ7 UXS1_HUMANUDP-glucuronic acid decarboxylase 1 (EC 4.1.1.35) (UDP-glucuronatedecarboxylase 1) UXS1 420 (UGD) (UXS-1) UNQ2538/PRO6079 Q86Y38XYLT1_HUMAN Xylosyltransferase 1 (EC 2.4.2.26) (PeptideO-xylosyltransferase 1) (Xylosyltransferase I) XYLT1 XT1 959 (XT-I)(XylT-I) P17861 XBP1_HUMAN X-box-binding protein 1 (XBP-1)(Tax-responsive element-binding protein 5) (TREB-5) XBP1 TREB5 XBP2 261[Cleaved into: X-box-binding protein 1, cytoplasmic form; X-box-bindingprotein 1, luminal form] O75063 XYLK_HUMAN Glycosaminoglycanxylosylkinase (EC 2.7.1.—) (Xylose kinase) FAM20B KIAA0475 409 Q8NBI6XXLT1_HUMAN Xyloside xylosyltransferase 1 (EC 2.4.2.n3) (UDP-xylose:alpha-xyloside alpha-1,3- XXYLT1 C3orf21 393 xylosyltransferase)PSEC0251 Q9H1B5 XYLT2_HUMAN Xylosyltransferase 2 (EC 2.4.2.26) (PeptideO-xylosyltransferase 1) (Xylosyltransferase XYLT2 XT2 865 II) (XT-II)(XylT-II) UNQ3058/PRO9878 A8MXE2 YI036_HUMAN Putative UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase LOC100288842 369 (EC2.4.1.—) (Putative UDP-GlcNAc: betaGalbeta-1,3-N-acetylglucosaminyltransferase LOC402377) (UDP-GlcNAc: betaGalbeta-1,3-N-acetylglucosaminyltransferase 5 pseudogene) Q5STJ7Q5STJ7_HUMAN Hexosyltransferase (EC 2.4.1.—) B3GALT4 378 hCG_17511A0A090N7X6 A0A090N7X6_HUMAN PolypeptideN-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GALNT11 608acetylgalactosaminyltransferase) hCG_1990637 tcag7.1057 Q5Q0U2Q5Q0U2_HUMAN Fucosyltransferase 9 (EC 2.4.1.152) (Fucosyltransferase 9(Alpha (1,3) FUT9 hCG_16703 359 fucosyltransferase), isoform CRA_a)(cDNA, FLJ95882, Homo sapiens fucosyltransferase 9 (alpha (1,3)fucosyltransferase) (FUT9), mRNA) A8K9Q8 A8K9Q8_HUMAN Hexosyltransferase(EC 2.4.1.—) hCG_2018639 384 A8K737 A8K737_HUMAN Fucosyltransferase(Fucosyltransferase 3 (Galactoside 3(4)-L-fucosyltransferase, Lewis FUT3hCG_1645372 361 blood group)) (cDNA FLJ78078, highly similar to Humanalpha (1,3/1,4) fucosyltransferase (FUT3)) G3V1S6 G3V1S6_HUMANPolypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDPGALNT2 533 acetylgalactosaminyltransferase) hCG_15927 Q58A54Q58A54_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—)(Protein-UDP GalNAc-T18 607 acetylgalactosaminyltransferase) GALNT18GALNTL4 hCG_1991780 A0A087WY64 A0A087WY64_HUMAN Hexosyltransferase (EC2.4.1.—) B3GALNT2 92 A3KLL5 A3KLL5_HUMAN Sodium/potassium-transportingATPase subunit beta ATP1B1 303 hCG_37798 Q2L4S5 Q2L4S5_HUMAN PolypeptideN-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GALNT19WBSCR17 598 acetylgalactosaminyltransferase) hCG_19354 tcag7.519 B7ZKW0B7ZKW0_HUMAN Sodium/potassium-transporting ATPase subunit beta ATP1B4314 Q9P1W6 Q9P1W6_HUMAN Alpha-(1,3/1,4)-fucosyltransferase (cDNA,FLJ94139, highly similar to Homo sapiens FUT3 361 fucosyltransferase 3(galactoside 3(4)-L-fucosyltransferase, Lewis blood group included)(FUT3), mRNA) A0A024RC48 A0A024RC48_HUMAN PolypeptideN-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GALNT1 559acetylgalactosaminyltransferase) hCG_2042960 D3DNF9 D3DNF9_HUMANSodium/potassium-transporting ATPase subunit beta ATP1B3 265 hCG_19938A0A024RBT1 A0A024RBT1_HUMAN Hexosyltransferase (EC 2.4.1.—) hCG_2016450378 D3DQI7 D3DQI7_HUMAN Polypeptide N-acetylgalactosaminyltransferase(EC 2.4.1.—) (Protein-UDP GALNT10 506 acetylgalactosaminyltransferase)hCG_36809 B7Z5G5 B7Z5G5_HUMAN PolypeptideN-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP 527acetylgalactosaminyltransferase) B5B9M4 B5B9M4_HUMAN FucosyltransferaseFUT3 361 Q68VJ8 Q68VJ8_HUMAN PolypeptideN-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GALNT16GALNTL1 hCG_21969 558 acetylgalactosaminyltransferase) E7EVF0E7EVF0_HUMAN Hexosyltransferase (EC 2.4.1.—) B3GALNT1 91 B2R8J0B2R8J0_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—)(Protein-UDP 633 acetylgalactosaminyltransferase) C9J368 C9J368_HUMANHexosyltransferase (EC 2.4.1.—) (Fragment) B3GNT5 50 B2RC53 B2RC53_HUMANcDNA, FLJ95856, highly similar to Homo sapiens fucosyltransferase 11(alpha (1,3) 492 fucosyltransferase) (FUT11), mRNA A8KAJ7 A8KAJ7_HUMANPolypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP559 acetylgalactosaminyltransferase) Q8NHI0 Q8NHI0_HUMANHexosyltransferase (EC 2.4.1.—) 67 B4DIE4 B4DIE4_HUMANHexosyltransferase (EC 2.4.1.—) 91 B3KT16 B3KT16_HUMAN PolypeptideN-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP 372acetylgalactosaminyltransferase) B7ZKV9 B7ZKV9_HUMANSodium/potassium-transporting ATPase subunit beta ATP1B4 322 Q6RC02Q6RC02_HUMAN Hexosyltransferase (EC 2.4.1.—) 102 A0A087WV18A0A087WV18_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC2.4.1.—) (Protein-UDP WBSCR17 519 acetylgalactosaminyltransferase)R4X5Z0 R4X5Z0_HUMAN Hexosyltransferase (EC 2.4.1.—) B3GALNT1 83 C9JGI4C9JGI4_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—)(Protein-UDP GALNT15 617 acetylgalactosaminyltransferase) Q24JS2Q24JS2_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—)(Protein-UDP GALNT6 622 acetylgalactosaminyltransferase) B7ZKV8B7ZKV8_HUMAN Sodium/potassium-transporting ATPase subunit beta ATP1B4357 I3L1V9 I3L1V9_HUMAN Sodium/potassium-transporting ATPase subunitbeta (Fragment) ATP1B2 167 B4DLS4 B4DLS4_HUMAN cDNA FLJ55721, highlysimilar to Homo sapiens fucosyltransferase 10 (alpha (1,3) 521fucosyltransferase) (FUT10), mRNA Q05BM8 Q05BM8_HUMAN PolypeptideN-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GALNT1 499acetylgalactosaminyltransferase) A0A087X115 A0A087X115_HUMAN PolypeptideN-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GALNTL6 417acetylgalactosaminyltransferase) J3KNN1 J3KNN1_HUMAN PolypeptideN-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GALNT9 603acetylgalactosaminyltransferase) B3KTQ4 B3KTQ4_HUMAN Hexosyltransferase(EC 2.4.1.—) 331 B3KY85 B3KY85_HUMAN PolypeptideN-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP 556acetylgalactosaminyltransferase) E7EVS2 E7EVS2_HUMAN Hexosyltransferase(EC 2.4.1.—) (Fragment) B3GALNT1 111 B7Z9S8 B7Z9S8_HUMANSodium/potassium-transporting ATPase subunit beta 247 B3W6H0B3W6H0_HUMAN Fucosyltransferase FUT3 361 B3GVC1 B3GVC1_HUMANFucosyltransferase FUT3 361 Q8TDY1 Q8TDY1_HUMAN Hexosyltransferase (EC2.4.1.—) OK/KNS-cl.1 204 Q6P7E6 Q6P7E6_HUMAN Fucosyltransferase 6 (Alpha(1,3) fucosyltransferase) FUT6 359 F8VUJ3 F8VUJ3_HUMAN PolypeptideN-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP POC1B-GALNT4575 acetylgalactosaminyltransferase) B3KNV8 B3KNV8_HUMAN PolypeptideN-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP 607acetylgalactosaminyltransferase) Q7L9G8 Q7L9G8_HUMAN Hexosyltransferase(EC 2.4.1.—) 331 Q6RC00 Q6RC00_HUMAN Hexosyltransferase (EC 2.4.1.—) 331M0QX58 M0QX58_HUMAN Hexosyltransferase (EC 2.4.1.—) (Fragment) B3GNT3127 B4E056 B4E056_HUMAN cDNA FLJ56031, highly similar to Homo sapiensfucosyltransferase 10 (alpha (1,3) 529 fucosyltransferase) (FUT10), mRNAQ58A70 Q58A70_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC2.4.1.—) (Protein-UDP GalNAc-T10 581 acetylgalactosaminyltransferase)B3KQP5 B3KQP5_HUMAN Hexosyltransferase (EC 2.4.1.—) 378 B3KRF8B3KRF8_HUMAN Hexosyltransferase (EC 2.4.1.—) 378 Q6RBZ9 Q6RBZ9_HUMANHexosyltransferase (EC 2.4.1.—) 319 I3L3J8 I3L3J8_HUMANSodium/potassium-transporting ATPase subunit beta (Fragment) ATP1B2 172D7UNW5 D7UNW5_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC2.4.1.—) (Protein-UDP GALNT6 622 acetylgalactosaminyltransferase) Q49AT3Q49AT3_HUMAN Hexosyltransferase (EC 2.4.1.—) B3GALNT1 331 B4DL56B4DL56_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—)(Protein-UDP 603 acetylgalactosaminyltransferase) Q6RC01 Q6RC01_HUMANHexosyltransferase (EC 2.4.1.—) 144 B3KP58 B3KP58_HUMAN PolypeptideN-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP 460acetylgalactosaminyltransferase) E9PJ79 E9PJ79_HUMAN Hexosyltransferase(EC 2.4.1.—) (Fragment) B3GNT6 121 B2R7V3 B2R7V3_HUMAN cDNA, FLJ93618,highly similar to Homo sapiens fucosyltransferase 6 (alpha (1,3) 359fucosyltransferase) (FUT6), mRNA C9J0F8 C9J0F8_HUMAN Hexosyltransferase(EC 2.4.1.—) (Fragment) B3GALNT1 65 E5D8G0 E5D8G0_HUMAN PolypeptideN-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP 601acetylgalactosaminyltransferase) B3KQT5 B3KQT5_HUMAN Hexosyltransferase(EC 2.4.1.—) 372 C9J5K2 C9J5K2_HUMAN Hexosyltransferase (EC 2.4.1.—)(Fragment) B3GNT5 81 C9J8U7 C9J8U7_HUMAN Hexosyltransferase (EC 2.4.1.—)(Fragment) B3GALNT1 54 H0YAH3 H0YAH3_HUMAN PolypeptideN-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GALNT7 454acetylgalactosaminyltransferase) (Fragment) C9JD16 C9JD16_HUMANHexosyltransferase (EC 2.4.1.—) (Fragment) B3GALNT1 58 B7Z6K2B7Z6K2_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—)(Protein-UDP 533 acetylgalactosaminyltransferase) B7Z5C5 B7Z5C5_HUMANPolypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP517 acetylgalactosaminyltransferase) Q58A53 Q58A53_HUMAN PolypeptideN-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GalNAc-T17598 acetylgalactosaminyltransferase) C9IYY0 C9IYY0_HUMANHexosyltransferase (EC 2.4.1.—) (Fragment) B3GNT5 62 A6NGH2 A6NGH2_HUMANSodium/potassium-transporting ATPase subunit beta 295 V9GYR2V9GYR2_HUMAN Sodium/potassium-transporting ATPase subunit beta(Fragment) ATP1B1 130 K7ENC0 K7ENC0_HUMAN Alpha-(1,3)-fucosyltransferase5 FUT5 374 R4X604 R4X604_HUMAN Hexosyltransferase (EC 2.4.1.—) B3GALNT1151 Q8NFN0 Q8NFN0_HUMAN Hexosyltransferase (EC 2.4.1.—) 181 Q58I18Q58I18_HUMAN Sodium/potassium-transporting ATPase subunit beta(Fragment) ATP1B3 137 R4X601 R4X601_HUMAN Hexosyltransferase (EC2.4.1.—) B3GALNT1 208 Q499Z2 Q499Z2_HUMAN Hexosyltransferase (EC2.4.1.—) (Fragment) B3GALT6 304 Q6LEU2 Q6LEU2_HUMANSodium/potassium-transporting ATPase subunit beta (Fragment) ATP1B1 303A0A0A0MS93 A0A0A0MS93_HUMAN Hexosyltransferase (EC 2.4.1.—) B3GALT5 314R4X5Z4 R4X5Z4_HUMAN Hexosyltransferase (EC 2.4.1.—) B3GALNT1 331 Q53F50Q53F50_HUMAN Hexosyltransferase (EC 2.4.1.—) (Fragment) 331 M0R199M0R199_HUMAN Hexosyltransferase (EC 2.4.1.—) (Fragment) B3GNT3 250

Table of Sequences in Appended Sequence Listing SEQ ID NO: IllustrativeDescription 1 DNA sequence of chimeric protein - comprising theextracellular domain of PD-1, followed by the hinge-CH2—CH3 domain ofhuman IgG4 and short linker, followed by the extracellular domain ofOX40L. 2 Amino acid sequence of chimeric protein - comprising theextracellular domain of PD-1, followed by the hinge-CH2—CH3 domain ofhuman IgG4 and short linker, followed by the extracellular domain ofOX40L. 3 Codon-optimized nucleic acid sequence, which is optimized forexpression by Chinese Hamster (CHO) cells 4 DNA sequence encoding theextracellular domain of PD-1 -Fc - the extracellular domain of TL1A 5Amino acid sequence encoded by a codon optimized nucleotide sequence ofSEQ ID NO: 4 6 Nucleotide sequence of construct (ex: A fusion proteinencoding the extracellular domain of BTLA, linked through an Fc toOX40L) 7 Amino acid sequence encoded by nucleotide sequence of SEQ IDNO: 6 8 DNA sequence of a fusion protein incorporating the extracellulardomain of TIGIT, linked via an Fc linker to OX40L 9 Amino acid sequenceencoded by a codon optimized nucleotide sequence of SEQ ID NO: 8 10 DNAsequence of a fusion protein incorporating the extracellular domain ofTIM3, linked through an Fc region to human OX40L 11 Amino acid sequenceencoded by a codon optimized nucleotide sequence of SEQ ID NO: 10 12Nucleotide sequence of the extracellular domain of CD172a adjoined withan Fc linker sequence to the extracellular domain of human OX40L 13Amino acid sequence encoded by a codon optimized nucleotide sequence ofSEQ ID NO: 12 14 Nucleotide sequence of the extracellular domain ofTMIGD2 adjoined with an Fc linker sequence to the extracellular domainof human OX40L 15 Amino acid sequence encoded by a codon optimizednucleotide sequence of SEQ ID NO: 14 16 mRNA sequence of human OX40L 17Amino acid sequence of human OX40L 18 Nucleic acid sequence of thehinge-CH2—CH3 Sequence from human IgG1 19 cDNA sequence of human PD-1 20Nucleic acid sequence of human PD-1-Fc-OX40L codon optimized forexpression by Chinese Hamster (CHO) cells 21 Nucleic acid sequence ofhuman PD-1-Fc-OX40L 22 Amino acid sequence of SL-279252 23 Amino acidsequence of Linker 24 Amino acid sequence of Linker 25 Amino acidsequence of Linker 26 Amino acid sequence of Linker 27 Amino acidsequence of Linker 28 Amino acid sequence of Linker 29 Amino acidsequence of Linker 30 Amino acid sequence of Linker 31 Amino acidsequence of Linker 32 Amino acid sequence of CD279 33 Amino acidsequence of CD172a 34 Amino acid sequence of BTLA 35 Amino acid sequenceof TIGIT 36 Amino acid sequence of TIM3 37 Amino acid sequence of CD20038 Amino acid sequence of TMIGD2 39 Amino acid sequence of VISTA 40Amino acid sequence of VSIG8 41 Amino acid sequence of BTNL2 42 Aminoacid sequence of TNFRSF1b 43 Amino acid sequence of CD276 44 Amino acidsequence of CD244 45 Amino acid sequence of LAG3 46 Amino acid sequenceof CSF1R 47 Amino acid sequence of TGFBR1 48 Amino acid sequence ofIL-10R 49 Amino acid sequence of CD40 50 Amino acid sequence of OX40 51Amino acid sequence of 41BB 52 Amino acid sequence of CTLA4 53 Aminoacid sequence of PD-L1 54 Amino acid sequence of PD-L2 55 Amino acidsequence of B7-H4 56 Amino acid sequence of OX40L 57 Amino acid sequenceof GITRL 58 Amino acid sequence of 41BBL 59 Amino acid sequence of TL1A60 Amino acid sequence of CD40L 61 Amino acid sequence of CD30L 62 Aminoacid sequence of TRAIL 63 Amino acid sequence of CD70 64 blank 65 blank66 blank 67 blank 68 blank 69 blank 70 Amino acid sequence of Linker -IgG4 hinge-CH2—CH3 71 Amino acid sequence of Linker - IgG4 hinge-CH2—CH3S228P 72 Amino acid sequence of Linker - IgG4 hinge-CH2—CD3 S228P FcRn73 Amino acid sequence of Joining Linker 74 Amino acid sequence ofJoining Linker 75 Amino acid sequence of Joining Linker 76 Amino acidsequence of Joining Linker 77 Amino acid sequence of Joining Linker 78Amino acid sequence of Joining Linker

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 32, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 33, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 34, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 35, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 36, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 37, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 38, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 39, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 40, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 41, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 42, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 43, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 44, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 45, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 46, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 47, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 48, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 49, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 50, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 51, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 52, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 53, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 54, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof. In various embodiments, the linkers (iii) or (iv) canbe substituted for the amino acid sequence of SEQ ID NOs: 23-31, or atleast 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) theamino acid sequence of SEQ ID NO: 55, or at least 90%, or 93%, or 95%,or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acidsequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59,SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO:64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99%identity thereto, and, optionally (iii) an Ig linker selected from theamino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72,or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identitythereto, where, also optionally, one or more of (i) and (ii) areconnected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ IDNO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, orvariants thereof.

In various embodiments, the linkers (iii) or (iv) can be substituted forthe amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%,or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises the aminoacid sequence of SEQ ID NO: 2, or at least 90%, or 93%, or 95%, or 97%,or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises the aminoacid sequence of SEQ ID NO: 5, or at least 90%, or 93%, or 95%, or 97%,or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises the aminoacid sequence of SEQ ID NO: 7, or at least 90%, or 93%, or 95%, or 97%,or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises the aminoacid sequence of SEQ ID NO: 9, or at least 90%, or 93%, or 95%, or 97%,or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises the aminoacid sequence of SEQ ID NO: 11, or at least 90%, or 93%, or 95%, or 97%,or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises the aminoacid sequence of SEQ ID NO: 13, or at least 90%, or 93%, or 95%, or 97%,or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises the aminoacid sequence of SEQ ID NO: 15, or at least 90%, or 93%, or 95%, or 97%,or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises the aminoacid sequence of SEQ ID NO: 22, or at least 90%, or 93%, or 95%, or 97%,or 98%, or 99% identity thereto.

EQUIVALENTS

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure as come within known or customary practice within theart to which the invention pertains and as may be applied to theessential features hereinbefore set forth and as follows in the scope ofthe appended claims.

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

INCORPORATION BY REFERENCE

All patents and publications referenced herein are hereby incorporatedby reference in their entireties.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.

As used herein, all headings are simply for organization and are notintended to limit the disclosure in any manner. The content of anyindividual section may be equally applicable to all sections.

1.-48. (canceled)
 49. A heterologous chimeric protein comprising: (a) a first domain comprising a portion of PD-1 that is capable of binding a PD-1 ligand, (b) a second domain comprising a portion of GITR ligand (GITRL) that is capable of binding an GITRL receptor, and (c) a linker linking the first domain and the second domain and comprising a hinge-CH2-CH3 Fc domain.
 50. The heterologous chimeric protein of claim 49, wherein the first domain comprises substantially all of the extracellular domain of PD-1 and the second domain comprises substantially all of the extracellular domain of GITRL.
 51. The heterologous chimeric protein of claim 49, wherein the heterologous chimeric protein is capable of inhibiting an immunosuppressive signal.
 52. The heterologous chimeric protein of claim 49, wherein the heterologous chimeric protein is capable of: (a) reducing or eliminating an immune inhibitory signal when the portion of PD-1 is bound to its ligand and/or (b) increasing or activating an immune stimulatory signal when the portion of GITRL is bound to its receptor.
 53. The heterologous chimeric protein of claim 49, wherein the PD-1 ligand is PD-L1.
 54. The heterologous chimeric protein of claim 49, wherein the GITRL receptor is GITR.
 55. The heterologous chimeric protein of claim 49, wherein the heterologous chimeric protein is capable of simultaneously binding the PD-1 ligand and the GITRL receptor, wherein the PD-1 ligand is PD-L1, and the GITRL receptor is GITR.
 56. The heterologous chimeric protein of claim 49, wherein the heterologous chimeric protein is capable of reducing the ability of CD4+FoxP3+ regulatory T cells to suppress the proliferation of conventional CD4+ or CD8+ T cells.
 57. The heterologous chimeric protein of claim 49, wherein the heterologous chimeric protein is capable of enhancing tumor killing activity by T cells.
 58. The heterologous chimeric protein of claim 49, wherein the heterologous chimeric protein is capable of providing a sustained immunomodulatory effect.
 59. The heterologous chimeric protein of claim 49, wherein the linker comprises a hinge-CH2-CH3 Fc domain derived from IgG4.
 60. The heterologous chimeric protein of claim 59, wherein the hinge-CH2-CH3 Fc domain is derived from human IgG4.
 61. The heterologous chimeric protein of claim 49, wherein the chimeric protein is expressed by a mammalian host cell as a secretable and functional single polypeptide chain.
 62. The heterologous chimeric protein of claim 49, wherein the portion of PD-1 is at least 95% identical to the amino acid sequence of SEQ ID NO:
 32. 63. The heterologous chimeric protein of claim 49, wherein the portion of GITRL is at least 95% identical to the amino acid sequence of SEQ ID NO:
 57. 64. The heterologous chimeric protein of claim 49, wherein the linker comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 71 or SEQ ID NO:
 72. 65. The heterologous chimeric protein of claim 49, wherein (a) the first domain comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 32, (b) the second domain comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 57, and (c) the linker comprises an amino acid sequence that is at least 95% identical to SEQ ID NO:
 72. 66. An expression vector, comprising a nucleic acid encoding the heterologous chimeric protein of claim
 49. 67. A host cell, comprising the expression vector of claim
 66. 68. A pharmaceutical composition, comprising a therapeutically effective amount of the heterologous chimeric protein of claim
 49. 69. A recombinant fusion protein comprising: (a) a first domain comprising a portion of PD-1 that is at least 95% identical to the amino acid sequence of SEQ ID NO: 32 and is capable of binding a PD-1 ligand, (b) a second domain comprising a portion of GITR ligand (GITRL) that is at least 95% identical to the amino acid sequence of SEQ ID NO: 57 and is capable of binding an GITRL receptor, and (c) a linker linking the first domain and the second domain.
 70. The recombinant fusion protein of claim 69, wherein the linker comprises an amino acid sequence that is at least 95% identical to SEQ ID NO:
 72. 71. The recombinant fusion protein of claim 69, wherein the heterologous fusion protein is capable of simultaneously binding the PD-1 ligand and the GITRL receptor, wherein the PD-1 ligand is PD-L1 and the GITRL receptor is GITR. 